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A significant problem in the diagnosis and management of traumatic spinal cord injury (tSCI) is the heterogeneity of secondary injury and the prediction of neurological outcome. Imaging biomarkers specific to myelin loss and inflammation after tSCI would enable detailed assessment of the pathophysiological processes underpinning secondary damage to the cord. Such biomarkers could be used to biologically stratify injury severity and better inform prognosis for neurological recovery. While much work has been done to establish magnetic resonance imaging (MRI) biomarkers for SCI in animal models, the relationship between imaging findings and the underlying pathology has been difficult to discern in human tSCI because of the paucity of human spinal cord tissue. We utilized post-mortem spinal cords from individuals who had a tSCI to examine this relationship by performing ex vivo MRI scans before histological analysis. We investigated the correlation between the histological distribution of myelin loss and inflammatory cells in the injured spinal cord and a number of myelin and inflammation-sensitive MRI measures: myelin water fraction (MWF), inhomogeneous magnetization transfer ratio (ihMTR), and diffusion tensor and diffusion kurtosis imaging-derived fractional anisotropy (FA) and axial, radial, and mean diffusivity (AD, RD, MD). The histological features were analyzed by staining with Luxol Fast Blue (LFB) for myelin lipids and Class II major histocompatibility complex (Class II MHC) and CD68 for microglia and macrophages. Both MWF and ihMTR were strongly correlated with LFB staining for myelin, supporting the use of both as biomarkers for myelin loss after SCI. A decrease in ihMTR was also correlated with the presence of Class II MHC positive immune cells. FA and RD correlated with both Class II MHC and CD68 and may therefore be useful biomarkers for inflammation after tSCI. Our work demonstrates the utility of advanced MRI techniques sensitive to biological tissue damage after tSCI, which is an important step toward using these MRI techniques in the clinic to aid in decision-making.

Abstract Individuals with SCI are severely affected by immune system changes, resulting in increased risk of infections and persistent systemic inflammation. While recent data support that immunological changes after SCI differ in the acute and chronic phases of living with SCI, only limited immunological phenotyping in humans is available. To characterize dynamic molecular and cellular immune phenotypes over the first year, we assess RNA (bulk-RNA sequencing), protein, and flow cytometry (FACS) profiles of blood samples from 12 individuals with SCI at 0-3 days and at 3, 6, and 12 months post injury (MPI) compared to 23 uninjured individuals (controls). We identified 967 differentially expressed (DE) genes in individuals with SCI (FDR <0.001) compared to controls. Within the first 6 MPI we detected a reduced expression of NK cell genes, consistent with reduced frequencies of CD56 bright , CD56 dim NK cells present at 12 MPI. Over 6MPI, we observed increased and prolonged expression of genes associated with inflammation (e.g. HMGB1, Toll-like receptor signaling) and expanded frequencies of monocytes acutely. Canonical T-cell related DE genes (e.g. FOXP3, TCF7, CD4) were upregulated during the first 6 MPI and increased frequencies of activated T cells at 3-12 MPI. Neurological injury severity was reflected in distinct whole blood gene expression profiles at any time after SCI, verifying a persistent 'neurogenic' imprint. Overall, 2876 DE genes emerge when comparing motor complete to motor incomplete SCI (ANOVA, FDR <0.05), including those related to neutrophils, inflammation, and infection. In summary, we identify a dynamic immunological phenotype in humans, including molecular and cellular changes which may provide potential targets to reduce inflammation, improve immunity, or serve as candidate biomarkers of injury severity.

Given the complexity of care necessitated after an acute traumatic spinal cord injury (SCI), it seems intuitively beneficial for such care to be delivered at hospitals with specialized SCI expertise. Demonstrating these benefits is not straightforward, however. We sought to determine whether specialized acute hospital care influenced the most fundamental outcomes after SCI: mortality within the first year of injury. We compared survival among patients with incomplete tSCI admitted to a single quaternary-level trauma hospital with a specialized acute SCI program versus those admitted to trauma hospitals without specialized acute SCI care. We performed a population-based retrospective observational cohort study using administrative and clinical data linked from multiple sources in British Columbia (BC) from 2001 to 2017. Among a cohort of 1920 patients, there were 193 deaths within one year. We failed to identify a significant overall benefit for survival after adjusting for potential confounders, and the confidence intervals (CIs) were compatible with both benefit and harm (odds ratio [OR] 1.01, 95% CI 0.17 to 6.11, p  = 0.99). Significant associations were observed with age greater than 65 (OR 4.92, 95% CI 1.66 to 14.57, p  < 0.01), Charlson Comorbidity Index (OR 1.61, 95% CI 1.42 to 1.83, p  < 0.01), Injury Severity Score (OR 1.08, 95% CI 1.06 to 1.11, p  < 0.01), and traumatic brain injury (OR 2.12, 95% CI 1.32 to 3.41, p < 0.01). Among patients with acute tSCI, admission to a hospital with specialized acute SCI care was not associated with improved overall one-year survival. Subgroup analyses, however, suggested heterogeneity of effects, with little benefit for older patients with less polytrauma and substantial benefit for younger patients with greater polytrauma.

Intraparenchymal hemorrhage (IPH) after a traumatic injury has been associated with poor neurological outcomes. Although IPH may result from the initial mechanical trauma, the blood and its breakdown products have potentially deleterious effects. Further, the degree of IPH has been correlated with injury severity and the extent of subsequent recovery. Therefore, accurate evaluation and quantification of IPH following traumatic spinal cord injury (SCI) is important to define treatments' effects on IPH progression and secondary neuronal injury. Imaging modalities, such as magnetic resonance imaging (MRI) and ultrasound (US), have been explored by researchers for the detection and quantification of IPH following SCI. Both quantitative and semiquantitative MRI and US measurements have been applied to objectively assess IPH following SCI, but the optimal methods for doing so are not well established. Studies in animal SCI models (rodent and porcine) have explored US and histological techniques in evaluating SCI and have demonstrated the potential to detect and quantify IPH. Newer techniques using machine learning algorithms (such as convolutional neural networks [CNN]) have also been studied to calculate IPH volume and have yielded promising results. Despite long-standing recognition of the potential pathological significance of IPH within the spinal cord, quantifying IPH with MRI or US is a relatively new area of research. Further studies are warranted to investigate their potential use. Here, we review the different and emerging quantitative MRI, US, and histological approaches used to detect and quantify IPH following SCI.

Over the past few decades, tremendous advances have been made in our understanding of the biological changes underpinning the devastating impairment of traumatic spinal cord injury (SCI). Much of this scientific research has focused on animal models of SCI, and comparatively little has been done in human SCI, largely because biospecimens from human SCI patients are not readily available. This paucity of scientific enquiry in human SCI represents an important void in the spectrum of translational research, as biological differences between animal models and the human condition need to be considered in the pre-clinical development of therapeutic approaches. The International Spinal Cord Injury Biobank (ISCIB) is a multi-user biorepository with the mission of accelerating therapeutic development in traumatic SCI through improved biological understanding of human injury, and the vision of serving as a global research resource where human SCI biospecimens are shared with researchers around the world. Aligned with internationally recognized best practices, ISCIB's formal governance structure and standard operating procedures have earned it official biobank certification through the Canadian Tissue Repository Network. Herein, we describe the translational research gap that ISCIB is helping to fill; its structure, governance and certification; how data and samples are accrued, processed and stored; and finally, the process through which samples and data are shared with global researchers. The purpose of this paper describing ISCIB is to serve as an introductory guidance document for the wider community of SCI researchers. By helping researchers understand the contents of ISCIB and the process of accessing biospecimens, we seek to further ISCIB's vision as being a resource for human and translational research in SCI, with the ultimate goal of finding disease-modifying therapies for this disabling condition.

After acute traumatic spinal cord injury (SCI), the spinal cord can swell to fill the subarachnoid space and become compressed by the surrounding dura. In a porcine model of SCI, we performed a duraplasty to expand the subarachnoid space around the injured spinal cord and evaluated how this influenced acute intraparenchymal hemodynamic and metabolic responses, in addition to histological and behavioral recovery. Female Yucatan pigs underwent a T10 SCI, with or without duraplasty. Using microsensors implanted into the spinal cord parenchyma, changes in blood flow (ΔSCBF), oxygenation (ΔPO 2 ), and spinal cord pressure (ΔSCP) during and after SCI were monitored, alongside metabolic responses. Behavioral recovery was tested weekly using the Porcine Injury Behavior Scale (PTIBS). Thereafter, spinal cords were harvested for tissue sparing analyses. In both duraplasty and non-animals, the ΔSCP increased ∼5 mm Hg in the first 6 h post-injury. After this, the SCP appeared to be slightly reduced in the duraplasty animals, although the group differences were not statistically significant after controlling for injury severity in terms of impact force. During the first seven days post-SCI, the ΔSCBF or ΔPO 2 values were not different between the duraplasty and control animals. Over 12 weeks, there was no improvement in hindlimb locomotion as assessed by PTIBS scores and no reduction in tissue damage at the injury site in the duraplasty animals. In our porcine model of SCI, duraplasty did not provide any clear evidence of long-term behavioral or tissue sparing benefit after SCI.

Accurate safety information in published clinical trials guides the assessment of risk-benefit, as well as the design of future clinical trials. Comprehensive reporting of adverse events, toxicity, and discontinuations from acute spinal cord injury clinical trials is an essential step in this process. Here, we sought to assess the degree of "satisfactoriness" of reporting in past clinical trials in spinal cord injury. A review of citations from MEDLINE and EMBASE identified eligible clinical trials in acute (within 30 days) spinal cord injury. English language studies, published between 1980 and 2020, with sensory, motor, or autonomic neurological assessments as the primary outcome measure were eligible for inclusion. Criteria were then established to qualify the safety reporting as satisfactory (i.e., distinguished severe/life-threatening events), partially satisfactory, or unsatisfactory (i.e., only mentioned in general statements, or reported but without distinguishing severe events). A total of 40 trials were included. Satisfactory reporting for clinical adverse events was observed in 30% of trials; partially satisfactory was achieved by 10% of the trials, and the remaining 60% were unsatisfactory. The majority of trials were determined to be unsatisfactory for the reporting of laboratory-defined toxicity (82.5%); only 17.5% were satisfactory. Discontinuations were satisfactorily reported for the majority of trials (80%), with the remaining partially satisfactory (5%) or unsatisfactory (15%). Reporting of safety in clinical trials for acute spinal cord injury is suboptimal. Due to the complexities of acute spinal cord injury (e.g., polytrauma, multiple systems affected), tailored and specific standards for tracking adverse events and safety reporting should be established.

Acute traumatic spinal cord injury (SCI) can result in severe, lifelong neurological deficits. After SCI, Rho activation contributes to collapse of axonal growth cones, failure of axonal regeneration, and neuronal loss. This randomized, double-blind, placebo-controlled phase 2b/3 study evaluated the efficacy and safety of Rho inhibitor VX-210 (9 mg) in patients after acute traumatic cervical SCI. The study enrolled patients 14-75 years of age with acute traumatic cervical SCIs, C4-C7 (motor level) on each side, and American Spinal Injury Association Impairment Scale (AIS) Grade A or B who had spinal decompression/stabilization surgery commencing within 72 h after injury. Patients were randomized 1:1 with stratification by age (<30 vs. ≥30 years) and AIS grade (A vs. B with sacral pinprick preservation vs. B without sacral pinprick preservation). A single dose of VX-210 or placebo in fibrin sealant was administered topically onto the dura over the site of injury during decompression/stabilization surgery. Patients were evaluated for medical, neurological, and functional changes, and serum was collected for pharmacokinetics and immunological analyses. Patients were followed up for up to 12 months after treatment. A planned interim efficacy-based futility analysis was conducted after ∼33% of patients were enrolled. The pre-defined futility stopping rule was met, and the study was therefore ended prematurely. In the final analysis, the primary efficacy end-point was not met, with no statistically significant difference in change from baseline in upper-extremity motor score at 6 months after treatment between the VX-210 (9-mg) and placebo groups. This work opens the door to further improvements in the design and conduct of clinical trials in acute SCI.

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain >8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome.

There is an increasing need to develop approaches that will not only improve the clinical management of neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI), but also advance therapeutic interventions aimed at recovering bladder function. Although pre-clinical research frequently employs rodent SCI models, large animals such as the pig may play an important translational role in facilitating the development of devices or treatments. Therefore, the objective of this study was to develop a urodynamics protocol to characterize NLUTD in a porcine model of SCI. An iterative process to develop the protocol to perform urodynamics in female Yucatan minipigs began with a group of spinally intact, anesthetized pigs. Subsequently, urodynamic studies were performed in a group of awake, lightly restrained pigs, before and after a contusion-compression SCI at the T2 or T9-T11 spinal cord level. Bladder tissue was obtained for histological analysis at the end of the study. All anesthetized pigs had bladders that were acontractile, which resulted in overflow incontinence once capacity was reached. Uninjured, conscious pigs demonstrated appropriate relaxation and contraction of the external urethral sphincter during the voiding phase. SCI pigs demonstrated neurogenic detrusor overactivity and a significantly elevated post-void residual volume. Relative to the control, SCI bladders were heavier and thicker. The developed urodynamics protocol allows for repetitive evaluation of lower urinary tract function in pigs at different time points post-SCI. This technique manifests the potential for using the pig as an intermediary, large animal model for translational studies in NLUTD.

High-level spinal cord injury (SCI) can disrupt cardiovascular autonomic function. However, the evolution of cardiovascular autonomic function in the acute phase following injury is unknown. We evaluated the timing, severity, progression, and implications of cardiovascular autonomic injury following acute SCI. We tested 63 individuals with acute traumatic SCI (aged 48 ± 2 years) at five time-points: <2 weeks, and 1, 3, 6-12, and >12 months post-injury. Supine beat-to-beat systolic arterial pressure (SAP) and R-R interval (RRI) were recorded and low-frequency variability (LF SAP and LF RRI) determined. Cross-spectral analyses were used to determine baroreflex function (low frequency) and cardiorespiratory interactions (high frequency). Known electrocardiographic (ECG) markers for arrhythmia and self-reported symptoms of cardiovascular dysfunction were determined. Comparisons were made with historical data from individuals with chronic SCI and able-bodied controls. Most individuals had high-level (74%) motor/sensory incomplete (63%) lesions. All participants had decreased LF SAP at <2 weeks (2.22 ± 0.65 mm Hg 2 ). Autonomic injury was defined as high-level SCI with LF SAP <2 mm Hg 2 . Two distinct groups emerged by 1 month: autonomically complete SCI with sustained low LF SAP (0.76 ± 0.17 mm Hg 2 ) and autonomically incomplete SCI with increased LF SAP (5.46 ± 1.0 mm Hg 2 , p  < 0.05). Autonomically complete injuries did not recover over time. Cardiovascular symptoms were prevalent and worsened with time, especially in those with autonomically complete lesions, and chronic SCI. Baroreflex function and cardiorespiratory interactions were impaired after SCI. Risk of arrhythmia increased immediately after SCI, and remained elevated throughout the acute phase. Acute SCI is associated with severe cardiovascular dysfunction. LF SAP provides a simple, non-invasive, translatable, quantitative assessment of autonomic function, and is most informative 1 month after injury.

As the incidence of traumatic spinal cord injury (tSCI) in the elderly rises, clinicians are increasingly faced with difficult discussions regarding aggressiveness of management, likelihood of recovery, and survival. Our objective was to outline risk factors associated with in-hospital mortality in elderly surgical and non-surgical patients following tSCI and to determine those unlikely to have a favorable outcome. Data from elderly patients (≥ 65 years of age) in the Canadian Rick Hansen SCI Registry from 2004 to 2017 were analyzed using descriptive analysis. Survival and mortality groups in each of the surgical and non-surgical group were compared to explore factors associated with in-hospital mortality and their impact, using logistical regression. Of 1340 elderly patients, 1018 had surgical data with 826 having had surgery. In the surgical group, the median time to death post-injury was 30 days with 75% dying within 50 days compared with 7 days and 20 days, respectively, in the non-surgical group. Significant predictors for in-hospital mortality following surgery are age, comorbidities, neurological injury severity (American Spinal Injury Association [ASIA] Impairment Scale [AIS]), and ventilation status. The odds of dying 50 days post-surgery are six times higher for patients ≥77 years of age versus those 65-76 years of age, five times higher for those with AIS A versus those with AIS B/C/D, and seven times higher for those who are ventilator dependent. An expected probability of dying within 50 days post-surgery was determined using these results. In-hospital mortality in the elderly after tSCI is high. The trend with age and time to death and the significant predictors of mortality identified in this study can be used to inform clinical decision making and discussions with patients and their families.

Yucatan miniature pigs (YMPs) are similar to humans in spinal cord size as well as physiological and neuroanatomical features, making them a useful model for human spinal cord injury. However, little is known regarding pig gait kinematics, especially on a treadmill. In this study, 12 healthy YMPs were assessed during bipedal and/or quadrupedal stepping on a treadmill at six speeds (1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 km/h). Kinematic parameters, including limb coordination and proximal and distal limb angles, were measured. Findings indicate that YMPs use a lateral sequence footfall pattern across all speeds. Stride and stance durations decreased with increasing speed whereas swing duration showed no significant change. Across all speeds assessed, no significant differences were noted between hindlimb stepping parameters for bipedal or quadrupedal gait with the exception of distal limb angular kinematics. Specifically, significant differences were observed between locomotor tasks during maximum flexion (quadrupedal > bipedal), total excursion (bipedal > quadrupedal), and the phase relationship between the timing of maximum extension between the right and left hindlimbs (bipedal > quadrupedal). Speed also impacted maximum flexion and right-left phase relationships given that significant differences were found between the fastest speed (3.5 km/h) relative to each of the other speeds. This study establishes a methodology for bipedal and quadrupedal treadmill-based kinematic testing in healthy YMPs. The treadmill approach used was effective in recruiting primarily the spinal circuitry responsible for the basic stepping patterns as has been shown in cats. We recommend 2.5 km/h (0.7 m/sec) as a target walking gait for pre-clinical studies using YMPs, which is similar to that used in cats.

One of the only currently available treatment options to potentially improve neurological recovery after acute spinal cord injury (SCI) is augmentation of mean arterial blood pressure (MAP) to promote blood flow and oxygen delivery to the injured cord. However, to optimize such hemodynamic management, clinicians require a method to monitor the physiological effects of these MAP alterations within the injured cord. Therefore, we investigated the feasibility and effectiveness of using a novel optical sensor, based on near-infrared spectroscopy (NIRS), to monitor real-time spinal cord oxygenation and hemodynamics during the first 7 days post-injury in a porcine model of acute SCI. Six Yucatan miniature pigs underwent a T10 vertebral level contusion-compression injury. Spinal cord oxygenation and hemodynamics were continuously monitored by a minimally invasive custom-made NIRS sensor, and by invasive intraparenchymal (IP) probes to validate the NIRS measures. Episodes of MAP alteration and hypoxia were performed acutely after injury, and at 2 and 7 days post-injury to simulate the types of hemodynamic changes SCI patients experience after injury. The NIRS sensor demonstrated the ability to provide oxygenation and hemodynamic measurements over the 7-day post-SCI period. NIRS measures showed statistically significant correlations with each of the invasive IP measures and MAP changes during episodes of MAP alteration and hypoxia throughout the first week post-injury ( p  < 0.05). These results indicate that this novel NIRS system can monitor real-time changes in spinal cord oxygenation and hemodynamics over the first 7 days post-injury, and has the ability to detect local tissue changes that are reflective of systemic hemodynamic changes.

Current practice guidelines for acute spinal cord injury (SCI) recommend augmenting mean arterial blood pressure (MAP) for the first 7 days post-injury. After SCI, the cord may be compressed by the bone/ligaments of the spinal column, limiting regional spinal cord blood flow. Following surgical decompression, blood flow may be restored, and can potentially promote a "reperfusion" injury. The effects of MAP augmentation on the injured cord during the compressed and decompressed conditions have not been previously characterized. Here, we used our porcine model of SCI to examine the impact of MAP augmentation on blood flow, oxygenation, hydrostatic pressure, metabolism, and intraparenchymal (IP) hemorrhage within the compressed and then subsequently decompressed spinal cord. Yucatan mini-pigs underwent a T10 contusion injury followed by 2 h of sustained compression. MAP augmentation of ∼20 mm Hg was achieved with norepinephrine (NE). Animals received MAP augmentation either during the period of cord compression (CP), after decompression (DCP), or during both periods (CP-DCP). Probes to monitor spinal cord blood flow (SCBF), oxygenation, pressure, and metabolic responses were inserted into the cord parenchyma adjacent to the injury site to measure these responses. The cord was harvested for histological evaluation. MAP augmentation increased SCBF and oxygenation in all groups. In the CP-DCP group, spinal cord pressure steadily increased and histological analysis showed significantly increased hemorrhage in the spinal cord at and near the injury site. MAP augmentation with vasopressors may improve blood flow and reduce ischemia in the injured cord but may also induce undesirable increases in IP pressure and hemorrhage.

Although experience suggests a shift in the epidemiology of spinal cord injury (SCI) toward an older demographic, population studies are lacking. We aimed to evaluate (1) how the epidemiology and age profile of SCI have changed over time, and (2) how increased age impacts health outcomes up to 15 years post-injury. A population-based cohort study was performed in Ontario including adults diagnosed with traumatic SCI between 2002 and 2017. Older and younger SCI cohorts were created based on an age cutoff of 65 years. An older cohort of uninjured persons was matched to the older SCI cohort based on age, gender, and comorbidity status. Changes in crude incidence were reported as average annual percentage change (AAPC). Survival, readmissions, and costs were compared between the older and younger SCI cohorts as well as the between the older SCI and older matched uninjured cohorts. The incidence of SCI increased among females (AAPC 2.2; 95% confidence interval [CI] 0.1, 4.3), driven by a marked rise (4%/year) among elderly females (AAPC 4.3; 95% CI 0.1, 4.3). Although no change in incidence was detected for males, there was a trend toward increased incidence among older males (AAPC 1.2; 95% CI -1.3, 3.8). There were a higher proportion of cervical, incomplete, and fall-related injuries in the older than in younger SCI cohorts. Being over 65 years of age was associated with a sixfold increased risk of death (hazard ratio [HR] 5.75; 95% CI 4.72, 7.00). In comparison with the older uninjured cohort, the older SCI cohort had double the risk of death (HR 2.23; 95% CI 2.00, 2.50). Older persons with SCI had higher odds of readmission and higher costs. The incidence of SCI among the elderly is increasing, particularly among women. Prevention through fall reduction and education to improve outcomes are needed.

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 mm 2 at 24 weeks post-injury (wpi), and 5.29 ± 0.17 mm and 5.95 ± 0.24 mm 2 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.

Interventions to optimize spinal cord perfusion via support of mean arterial pressure (MAP) or spinal cord perfusion pressure (SCPP) are thought to play a critical role in the management of patients with acute traumatic spinal cord injuries, but there is ongoing controversy about efficacy and safety. We aimed to determine the effects of optimizing spinal cord perfusion on neurological recovery and risks for adverse events. We searched multiple databases for published and unpublished reports. Two reviewers independently screened articles, extracted data, and evaluated risk of bias. We synthesized data and evaluated confidence in anticipated treatment effects according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. We identified 20 eligible observational studies and 1 eligible randomized controlled trial. According to low or very low quality evidence, the effect of MAP support on neurological recovery after acute traumatic spinal cord injury is uncertain, and the use of vasopressors to support MAP may be associated with increased rates of predominantly cardiac adverse events. Increased SCPP appears likely to be associated with improved neurological recovery, but SCPP monitoring via intradural catheters at the anatomical site of injury may involve increased risks of cerebrospinal fluid leakage requiring revision surgery or pseudomeningocele. No study directly compared the effects of specific MAP goal ranges, SCPP ranges, SCPP monitoring techniques, or durations of treatment. Very low quality evidence suggests that norepinephrine may have less risk of adverse events than dopamine. The current literature is insufficient to make strong recommendations about interventions to support spinal cord perfusion via MAP or SCPP goals in patients with acute traumatic spinal cord injuries. Data are compatible with a variety of treatment decisions, and individualized approaches may be optimal. Further investigation to clarify the risks, benefits, and alternatives to MAP or SCPP support in this population is warranted.

Early decompression of the traumatically injured and persistently compressed spinal cord is intuitively beneficial for neurological outcome. Despite considerable pre-clinical evidence of a neurological benefit to early decompression, the effect of early surgical decompression in clinical spinal cord injury (SCI) remains less clear. The discrepancy between pre-clinical and clinical results may be due to differences between the biomechanical variables used in pre-clinical animal models and the biomechanical conditions occurring in clinical injuries. These pre-clinical variables include region of spinal cord, velocity of impact, and injury mechanism. In this study, the effect of velocity and duration of residual compression on injury severity were evaluated using a novel, rodent model of cervical dislocation SCI. Fifty-two male Sprague-Dawley rats were included in five groups: two timings of decompression (24 min, 240 min), two velocities (10 mm/sec, 500 mm/sec), and a sham group. All injuries involved a 1.45-mm dorsal dislocation of the C6 vertebra relative to C5 with subsequent residual compression of 0.8 mm. Animals were evaluated for motor function using the Martinez open field, grip strength, and grooming tests for 6 weeks post-injury. Immunohistochemistry and histology following sacrifice were conducted with counts for NeuN- and choline acetyltransferase (ChAT)-positive neurons, and length of cavitation. Behavioral testing and histological analysis revealed that injuries induced by the high velocity were consistently more severe than those induced by the low velocity, with behavioral correlations ranging between 0.46 and 0.58 ( p  < 0.05). Longer duration of residual compression did not produce significantly more severe injuries as measured by functional tests and histology. These findings demonstrate that the velocity of the initial traumatic impact may be a more important factor than duration of residual compression in determining SCI severity in a dislocation model of SCI.

Frailty negatively affects outcome in elective spine surgery populations. This study sought to determine the effect of frailty on patient outcome after traumatic spinal cord injury (tSCI). Patients with tSCI were identified from our prospectively collected database from 2004 to 2016. We examined effect of patient age, admission Total Motor Score (TMS), and Modified Frailty Index (mFI) on adverse events (AEs), acute length of stay (LOS), in-hospital mortality, and discharge destination (home vs. other). Subgroup analysis (for three age groups: <60, 61-75, and 76+ years), and multi-variable analysis was performed to investigate the impact of age, TMS, and mFI on outcome. For the 634 patients, the mean age was 50.3 years, 77% were male, and falls were the main cause of injury (46.5%). On bivariate analysis, mFI, age at injury, and TMS were predictors of AEs, acute LOS, and in-hospital mortality. After statistical adjustment, mFI was a predictor of LOS ( p  = 0.0375), but not of AEs ( p  = 0.1428) or in-hospital mortality ( p  = 0.1245). In patients <60 years of age, mFI predicted number of AEs, acute LOS, and in-hospital mortality. In those aged 61-75, TMS predicted AEs, LOS, and mortality. In those 76+ years of age, mFI no longer predicted outcome. Age, mFI, and TMS on admission are important determinants of outcome in patients with tSCI. mFI predicts outcomes in those <75 years of age only. The inter-relationship of advanced age and decreased physiological reserve is complex in acute tSCI, warranting further study. Identifying frailty in younger patients with tSCI may be useful for peri-operative optimization, risk stratification, and patient counseling.

The aim of this study was to determine the current trends in magnetic resonance imaging (MRI)/computed tomography (CT) utilization for spine trauma in various clinical scenarios. We conducted a survey across six AO regions and preformed pair-wise comparisons between responses obtained from different AO regions. The survey was sent to 5813 surgeons and had a 9.6% response rate with the majority being orthopedic followed by neurosurgeons. In a neurologically intact patient, the predominant imaging modality for all AO regions was CT. For patients with spinal cord injury (SCI), the predominant choice for all AO regions was CT + MRI + x-ray except North America, which was CT + MRI; pair-wise comparisons revealed significant differences involving LATAM (Latin America) versus (Asia-Pacific [APAC], Europe [EU], and Middle East [MEA]) and APAC versus (LATAM and North America [NA]). In a patient with incomplete SCI (ISCI) who presented within 4 h and had CT, the predominant choice for all AO regions was "forgo MRI and proceed to operating room (OR)." Similar to ISCI, in a patient with complete SCI, the predominant option for all AO regions was the same as ISCI, but the range was lower. Pair-wise comparisons noted significant differences between MEA and APAC, with both exhibiting differences compare to NA, LATAM, and EU for complete and ISCI. Most AO regions obtained post-operative MRI only if there was a new deficit. In summary, decisions about the use of a particular imaging modality across AO regions appears to be influenced by the neurological status of the patient upon admission and the presence of neurological deficits post-surgery. Type of residency training and fellowship training did not have an influence on choosing the appropriate imaging modality for both intact and impaired patients. Further study is needed to determine whether accessibility to MRI would change surgeons' attitude toward obtaining MRI in patients with SCI.

Despite advances in the treatment of acute spinal cord injury (SCI), measures to mitigate permanent neurological deficits in affected patients are limited. Immediate post-trauma hemodynamic management of patients, to maintain blood supply and improve oxygenation to the injured spinal cord, is currently one aspect of critical care which clinicians can utilize to improve neurological outcomes. However, without a way to monitor the response of spinal cord hemodynamics and oxygenation in real time, optimizing hemodynamic management is challenging and limited in scope. This study aims to investigate the feasibility and validity of using a miniaturized multi-wavelength near-infrared spectroscopy (NIRS) sensor for direct transdural monitoring of spinal cord oxygenation in an animal model of acute SCI. Nine Yorkshire pigs underwent a weight-drop T10 contusion-compression injury and received episodes of ventilatory hypoxia and alterations in mean arterial pressure (MAP). Spinal cord hemodynamics and oxygenation were monitored throughout by a non-invasive transdural NIRS sensor, as well as an invasive intraparenchymal sensor as a comparison. NIRS parameters of tissue oxygenation were highly correlated with intraparenchymal measures of tissue oxygenation. In particular, during periods of hypoxia and MAP alterations, changes of NIRS-derived spinal cord oxygenated hemoglobin and tissue oxygenation percentage corresponded well with the changes in spinal cord oxygen partial pressures measured by the intraparenchymal sensor. Our data confirm that during hypoxic episodes and as changes occur in the MAP, non-invasive NIRS can detect and measure real-time changes in spinal cord oxygenation with a high degree of sensitivity and specificity.

One of the challenges associated with conducting experiments in animal models of traumatic spinal cord injury (SCI) is inducing a consistent injury with minimal variability in the degree of tissue damage and resultant behavioral and biochemical outcomes. We evaluated how the variability in morphometry of the spinal cord and surrounding cerebrospinal fluid (CSF) contributes to the variability in behavioral and histological outcomes in our porcine model of SCI. Using intraoperative ultrasound imaging, spinal cord morphometry was assessed in seven Yucatan minipigs undergoing a weight-drop T10 contusion-compression injury. Bivariate and multi-variate analysis and modeling were used to identify native morphometrical determinants of interanimal variability in histological and behavioral outcomes. The measured biomechanical impact parameters did not correlate with the histological measures or hindlimb locomotor behavior (Porcine Thoracic Injury Behavior Scale). In contrast, clear associations were revealed between CSF layer morphometry and the amount of white matter and tissue sparing. Specifically, the dorsoventral diameter of the dural sac and ventral CSF space were strong predictors of behavioral and histological outcome and together explained ≥95.0% of the variance in these parameters. In addition, a dorsoventral diameter of the spinal cord less than 5.331 mm was a strong contributing factor to poor behavioral recovery over 12 weeks. These results indicate that interanimal variability in cord morphometry provides a potential biological explanation for the observed heterogeneity in histological and behavioral outcomes. Such knowledge is helpful for appropriately balancing experimental groups, and/or varying impact parameters to match cord and CSF layer dimensions for future studies.

Clinical trials of novel therapies for acute spinal cord injury (SCI) are challenging because variability in spontaneous neurologic recovery can make discerning actual treatment effects difficult. Unbiased Recursive Partitioning regression with Conditional Inference Trees (URP-CTREE) is a novel approach developed through analyses of a large European SCI database (European Multicenter Study about Spinal Cord Injury). URP-CTREE uses early neurologic impairment to predict achieved motor recovery, with potential to optimize clinical trial design by optimizing patient stratification and decreasing sample sizes. We performed external validation to determine how well a previously reported URP-CTREE model stratified patients into distinct homogeneous subgroups and predicted subsequent neurologic recovery in an independent cohort. We included patients with acute cervical SCI level C4-C6 from a prospective registry at a quaternary care center from 2004-2018 ( n  = 101) and applied the URP-CTREE model and evaluated Upper Extremity Motor Score (UEMS) recovery, considered correctly predicted when final UEMS scores were within a pre-specified threshold of 9 points from median; sensitivity analyses evaluated the effect of timing of baseline neurological examination. We included 101 patients, whose mean times from injury baseline and follow-up examinations were 6.1 days (standard deviation [SD] 17) and 235.0 days (SD 71), respectively. Median UEMS recovery was 7 points (interquartile range 2-12). One of the predictor variables was not statistically significant in our sample; one group did not fit progressively improving UEMS scores, and three of five groups had medians that were not significantly different from adjacent groups. Overall accuracy was 75%, but varied from 82% among participants whose examinations occurred at <12 h, to 64% at 12-24 h, and 58% at >24 h. A previous URP-CTREE model had limited ability to stratify an independent into homogeneous subgroups. Overall accuracy was promising, but may be sensitive to timing of baseline neurological examinations. Further evaluation of external validity in incomplete injuries, influence of timing of baseline examinations, and investigation of additional stratification strategies is warranted.

Spinal cord injury (SCI) is a devastating condition with variability in injury mechanisms and neurologic recovery. Spinal cord impairment after SCI is measured and classified by a widely accepted standard neurological examination. In the very acute stages post-injury, however, this examination is extremely challenging (and often impossible) to conduct and has modest prognostic value in terms of neurological recovery. The lack of objective tools to classify injury severity and predict outcome is a barrier for clinical trials and thwarts development of therapies for those with SCI. Biological markers (biomarkers) represent a promising, complementary approach to these challenges because they represent an unbiased approach to classify injury severity and predict neurological outcome. Identification of a suitable panel of molecular biomarkers would comprise a fundamental shift in how patients with acute SCI are evaluated, stratified, and treated in clinical trials. MicroRNA are attractive biomarker candidates in neurological disorders for several reasons, including their stability in biological fluids, their conservation between humans and model mammals, and their tissue specificity. In this study, we used next-generation sequencing to identify microRNA associated with injury severity within the cerebrospinal fluid (CSF) and serum of human patients with acute SCI. The CSF and serum samples were obtained 1-5 days post-injury from 39 patients with acute SCI (24 American Spinal Injury Association Impairment Scale [AIS] A, 8 AIS B, 7 AIS C) and from five non-SCI controls. We identified a severity-dependent pattern of change in microRNA expression in CSF and identified a set of microRNA that are diagnostic of baseline AIS classification and prognostic of neurological outcome six months post-injury. The data presented here provide a comprehensive description of the CSF and serum microRNA expression changes that occur after acute human SCI. This data set reveals microRNA candidates that warrant further evaluation as biomarkers of injury severity after SCI and as key regulators in other neurological disorders.

The course, treatment response, and recovery potential after acute traumatic spinal cord injury (SCI) have been shown to differ depending on the neurological level of injury. There are limited data focused on thoracic-level injuries, however. A cohort of 86 patients from the prospectively maintained North American Clinical Trials Network SCI registry were identified and studied to characterize the patterns of neurological recovery and to determine rates of acute hospital death and pulmonary complications. Regression analyses were used to examine the relationship between timing of surgery and administration of methylprednisolone on neurologic and clinical outcomes. Neurological conversion (≥1 American Spinal Injury Association Impairment Scale [AIS] grade improvement) was poorest for AIS grade A patients; 14.3% converted at last available follow-up (mean eight months). While rates of conversion were more optimistic for AIS-B patients (54.5%) and AIS C injuries (77.8%) at the same time point, none of the AIS grade D patients converted to AIS E. At last available follow-up (mean eight months), the magnitudes of lower motor extremity score (LEMS) change were highest for AIS C injuries (21.9 points), then AIS B (17.7 points), AIS D (16.4 points), and finally AIS A (2.5 points) (p < 0.05). Early surgical intervention (<24 h post-injury) was independently associated with an additional seven points in motor recovery and a 60% decreased incidence of pulmonary events (p < 0.05). Methylprednisolone administration was not an independent predictor of neurological outcome or pulmonary complications. Evaluation of this cohort obtained from a modern multi-center SCI registry provides an update on the natural history, acute death, and incidence of pulmonary complications after traumatic thoracic SCI. Although small sample size limited the extent of analyses possible, early surgical treatment was associated with significantly larger motor recovery and lower rates of pulmonary complications.

Acute traumatic spinal cord injury (SCI) entered the arena of prospective, randomized clinical trials almost 40 years ago, with the undertaking of the National Acute Spinal Cord Study (NASCIS) I trial. Since then, a number of clinical trials have been conducted in the field, spurred by the devastating physical, social, and economic consequences of acute SCI for patients, families, and society at large. Many of these have been controversial and attracted criticism. The current review provides a critical summary of select past and current clinical trials in SCI, focusing in particular on the findings of prospective, randomized controlled trials, the challenges and barriers encountered, and the valuable lessons learned that can be applied to future trials.

Current clinical guidelines recommend elevating the mean arterial blood pressure (MAP) to increase spinal cord perfusion in patients with acute spinal cord injury (SCI). This is typically achieved with vasopressors such as norepinephrine (NE) and phenylephrine (PE). These drugs differ in their pharmacological properties and potentially have different effects on spinal cord blood flow (SCBF), oxygenation (PO 2 ), and downstream metabolism after injury. Using a porcine model of thoracic SCI, we evaluated how these vasopressors influenced intraparenchymal SCBF, PO 2 , hydrostatic pressure, and metabolism within the spinal cord adjacent to the injury site. Yorkshire pigs underwent a contusion/compression SCI at T10 and were randomized to receive either NE or PE for MAP elevation of 20 mm Hg, or no MAP augmentation. Prior to injury, a combined SCBF/PO 2 sensor, a pressure sensor, and a microdialysis probe were inserted into the spinal cord adjacent to T10 at two locations: a "proximal" site and a "distal" site, 2 mm and 22 mm from the SCI, respectively. At the proximal site, NE and PE resulted in little improvement in SCBF during cord compression. Following decompression, NE resulted in increased SCBF and PO 2 , whereas decreased levels were observed for PE. However, both NE and PE were associated with a gradual decrease in the lactate to pyruvate (L/P) ratio after decompression. PE was associated with greater hemorrhage through the injury site than that in control animals. Combined, our results suggest that NE promotes better restoration of blood flow and oxygenation than PE in the traumatically injured spinal cord, thus providing a physiological rationale for selecting NE over PE in the hemodynamic management of acute SCI.

Biomarkers of acute human spinal cord injury (SCI) could provide a more objective measure of spinal cord damage and a better predictor of neurological outcome than current standardized neurological assessments. In SCI, there is growing interest in establishing biomarkers from cerebrospinal fluid (CSF) and from magnetic resonance imaging (MRI). Here, we compared the ability of CSF and MRI biomarkers to classify injury severity and predict neurological recovery in a cohort of acute cervical SCI patients. CSF samples and MRI scans from 36 acute cervical SCI patients were examined. From the CSF samples taken 24 h post-injury, the concentrations of inflammatory cytokines (interleukin [IL]-6, IL-8, monocyte chemotactic protein-1), and structural proteins (tau, glial fibrillary acidic protein, and S100β) were measured. From the pre-operative MRI scans, we measured intramedullary lesion length, hematoma length, hematoma extent, CSF effacement, cord expansion, and maximal spinal cord compression. Baseline and 6-month post-injury assessments of American Spine Injury Association Impairment Scale (AIS) grade and motor score were conducted. Both MRI measures and CSF biomarker levels were found to correlate with baseline injury grade, and in combination they provided a stronger model for classifying baseline AIS grade than CSF or MRI biomarkers alone. For predicting neurological recovery, the inflammatory CSF biomarkers best predicted AIS grade conversion, whereas structural biomarker levels best predicted motor score improvement. A logistic regression model utilizing CSF biomarkers alone had a 91.2% accuracy at predicting AIS conversion, and was not strengthened by adding MRI features or even knowledge of the baseline AIS grade. In a direct comparison of MRI and CSF biomarkers, the CSF biomarkers discriminate better between different injury severities, and are stronger predictors of neurological recovery in terms of AIS grade and motor score improvement. These findings demonstrate the utility of measuring the acute biological responses to SCI as biomarkers of injury severity and neurological prognosis.

Traumatic spinal cord injury (SCI) triggers many perturbations within the injured cord, such as decreased perfusion, reduced tissue oxygenation, increased hydrostatic pressure, and disrupted bioenergetics. While much attention is directed to neuroprotective interventions that might alleviate these early pathophysiologic responses to traumatic injury, the temporo-spatial characteristics of these responses within the injured cord are not well documented. In this study, we utilized our Yucatan mini-pig model of traumatic SCI to characterize intraparenchymal hemodynamic and metabolic changes within the spinal cord for 1 week post-injury. Animals were subjected to a contusion/compression SCI at T10. Prior to injury, probes for microdialysis and the measurement of spinal cord blood flow (SCBF), oxygenation (in partial pressure of oxygen; PaPO 2 ), and hydrostatic pressure were inserted into the spinal cord 0.2 and 2.2 cm from the injury site. Measurements occurred under anesthesia for 4 h post-injury, after which the animals were recovered and measurements continued for 7 days. Close to the lesion (0.2 cm), SCBF levels decreased immediately after SCI, followed by an increase in the subsequent days. Similarly, PaPO 2 plummeted, where levels remained diminished for up to 7 days post-injury. Lactate/pyruvate (L/P) ratio increased within minutes. Further away from the injury site (2.2 cm), L/P ratio also gradually increased. Hydrostatic pressure remained consistently elevated for days and negatively correlated with changes in SCBF. An imbalance between SCBF and tissue metabolism also was observed, resulting in metabolic stress and insufficient oxygen levels. Taken together, traumatic SCI resulted in an expanding area of ischemia/hypoxia, with ongoing physiological perturbations sustained out to 7 days post-injury. This suggests that our clinical practice of hemodynamically supporting patients out to 7 days post-injury may fail to address persistent ischemia within the injured cord. A detailed understanding of these pathophysiological mechanisms after SCI is essential to promote best practices for acute SCI patients.

Secondary complications of spinal cord injury (SCI) are a burden to affected individuals and the rest of society. There is limited evidence of the economic burden or cost of complications in SCI populations in Canada, however, which is necessary for comparative economic analyses and decision analytic modeling of possible solutions to these common health problems. Comparative economic analyses can inform resource allocation decisions, but the outputs are only as good as the inputs. In this article, new evidence of the excess or incremental costs of urinary tract infection (UTI) and pressure ulceration (PU) in acute traumatic SCI from an exploratory case series analysis of admissions to a Level I specialized Canadian spine facility (2008-2013) is presented. Participants in a national SCI registry were case-control matched (1:1) on the predicted probability of experiencing UTI or PU during initial acute SCI admission. The excess costs of UTI and PU are estimated as the mean of the differences in total direct acute SCI admission costs (length of stay, accommodation, nursing, pharmacy) from the perspective of the admitting facility between participants matched or paired on demographic and SCI characteristics. Even relatively minor UTI and PU, respectively, added an average of $7,790 (standard deviation [SD] $6,267) and $18,758 (SD $27,574) to the direct cost of acute SCI admission in 2013 Canadian dollars (CAD). This case series analysis established evidence of the excess costs of UTI and PU in acute SCI admissions, which will support decision-informing analyses in SCI.

Costs associated with initial hospitalization following spinal cord injury (SCI) are substantial, and a major driver of costs is the length of stay (LOS); that is, the time that the injured individual remains hospitalized prior to community reintegration. Our aim was to study the factors and variables that contribute to LOS following traumatic SCI. Modeling (process mapping of the SCI healthcare delivery system in Canada and discrete event simulation) and regression analysis using a national registry of individuals with acute traumatic SCI in Canada, existing databases, and peer-reviewed literature were used to examine the driver of LOS following traumatic SCI. In different jurisdictions, there is considerable variation in the definitions and methods used to determine LOS following SCI. System LOS can be subdivided into subcomponents, and progression through these is not unidirectional. Modeling reveals that healthcare organization and processes are important contributors to differences in LOS independent of patient demographics and injury characteristics. Future research is required to identify and improve understanding of contributors to LOS following traumatic SCI. This will help enhance system performance. Work in this area will be facilitated by the adoption of common terminology and definitions, as well as by the use of simulations and modeling.

There is worldwide geographic variation in the epidemiology of traumatic spinal cord injury (tSCI). The aim of this study was to determine whether environmental barriers, health status, and quality-of-life outcomes differ between patients with tSCI living in rural or urban settings, and whether patients move from rural to urban settings after tSCI. A cohort review of the Rick Hansen SCI Registry (RHSCIR) was undertaken from 2004 to 2012 for one province in Canada. Rural/urban setting was determined using postal codes. Outcomes data at 1 year in the community included the Short Form-36 Version 2 (SF36v2™), Life Satisfaction Questionnaire, Craig Hospital Inventory of Environmental Factors-Short Form (CHIEF-SF), Functional Independent Measure ® Instrument, and SCI Health Questionnaire. Statistical methodologies used were t test, Mann-Whitney U test, and Fisher's exact or χ 2 test. In the analysis, 338 RHSCIR participants were included; 65 lived in a rural setting and 273 in an urban setting. Of the original patients residing in a rural area at discharge,10 moved to an urban area by 1 year. Those who moved from a rural to urban area reported a lower SF-36v2™ Mental Component Score (MCS; p = 0.04) and a higher incidence of depression at 1 year (p = 0.04). Urban patients also reported a higher incidence of depression (p = 0.02) and a lower CHIEF-SF total score (p = 0.01) indicating fewer environmental barriers. No significant differences were found in other outcomes. Results suggest that although the patient outcomes are similar, some patients move from rural to urban settings after tSCI. Future efforts should target screening mental health problems early, especially in urban settings.

Current research indicates that more than half of patients with traumatic spinal cord injury (tSCI) experience delays in transfer and receive surgery >24 h post-injury. The objectives of this study were to determine the geographic distribution of tSCI in Canada relative to specialized treatment facilities, to assess clinical and logistical factors at play for indirect admissions to those facilities, and to explore differences in current time to admission and simulated scenarios in an attempt to assess the potential impact of changes to triage protocols. This study included data from 876 patients with tSCI enrolled in the prospectively collected acute Rick Hansen Spinal Cord Injury Registry (RHSCIR) between January 1, 2010 and December 31, 2013 for whom there were data on the location of their injury. Patients transported directly to a RHSCIR acute facility were more likely to reach the facility within 1 h of injury, whereas those transported indirectly were more likely to arrive 7 h later. Considering the injuries occurring within 40 km of a RHSCIR acute facility ( n  = 323), 249 patients (77%) were directly and 74 (23%) were indirectly admitted. In the multivariate regression analysis, only older age and longer road distance remained significantly associated with being indirectly admitted to a RHSCIR facility. Compared with the current status, the median time to admission decreased by 20% (3.5 h) in the 100% direct admission scenario, and increased by 102% (8.9 h) in the 100% indirect admission scenario.

Adverse events (AEs) are common during care in patients with traumatic spinal cord injury (tSCI). Increased risk of AEs is linked to patient factors including pre-existing comorbidities. Our aim was to examine the relationships between patient factors and common post-injury AEs, and identify potentially modifiable comorbidities. Adults with tSCI admitted to a Level I acute specialized spine center between 2006 and 2014 who were enrolled in the Rick Hansen SCI Registry (RHSCIR) and had AE data collected using the Spine Adverse Events Severity system were included. Patient demographic, neurological injury, and comorbidities data were obtained from RHSCIR. Potentially modifiable comorbidities were grouped into health-related conditions, substance use/withdrawal, and psychiatric conditions. Negative binomial regression and multiple logistic regression were used to model the impact of patient factors on the number of AEs experienced and the occurrence of the five previously identified common AEs, respectively. Of the 444 patients included in the study, 24.8% reported a health-related condition, 15.3% had a substance use/withdrawal condition, 8% reported having a psychiatric condition; and 79.3% experienced one or more AEs. Older age (p = 0.004) and more severe injuries (p < 0.001) were nonmodifiable independent variables significantly associated with increased AEs. The AEs experienced by patients were urinary tract infections (42.8%), pneumonia (39.2%), neuropathic pain (31.5%), delirium (18.2%), and pressure ulcers (11.0%). Risk of delirium increased in those with substance use/withdrawal; and pneumonia risk increased with psychiatric comorbidities. Opportunity exists to develop clinical algorithms that include these types of risk factors to reduce the incidence and impact of AEs.

Timely access and ongoing delivery of care and therapeutic interventions is needed to maximize recovery and function after traumatic spinal cord injury (tSCI). To ensure these decisions are evidence-based, access to consistent, reliable, and valid sources of clinical data is required. The Access to Care and Timing Model used data from the Rick Hansen SCI Registry (RHSCIR) to generate a simulation of healthcare delivery for persons after tSCI and to test scenarios aimed at improving outcomes and reducing the economic burden of SCI. Through model development, we identified knowledge gaps and challenges in the literature and current health outcomes data collection throughout the continuum of SCI care. The objectives of this article were to describe these gaps and to provide recommendations for bridging them. Accurate information on injury severity after tSCI was hindered by difficulties in conducting neurological assessments and classifications of SCI (e.g., timing), variations in reporting, and the lack of a validated SCI-specific measure of associated injuries. There was also limited availability of reliable data on patient factors such as multi-morbidity and patient-reported measures. Knowledge gaps related to structures (e.g., protocols) and processes (e.g., costs) at each phase of care have prevented comprehensive evaluation of system performance. Addressing these knowledge gaps will enhance comparative and cost-effectiveness evaluations to inform decision-making and standards of care. Recommendations to do so were: standardize data element collection and facilitate database linkages, validate and adopt more outcome measures for SCI, and increase opportunities for collaborations with stakeholders from diverse backgrounds.

Efforts to validate novel therapies in acute clinical trials for spinal cord injury (SCI) are impeded by the lack of objective quantitative measures that reflect injury severity and accurately predict neurological recovery. Therefore, a strong rationale exists for establishing neurochemical biomarkers that objectively quantify injury severity and predict outcome. Here, we conducted a targeted proteomics analysis of cerebrospinal fluid (CSF) samples derived from 29 acute SCI patients (American Spinal Injury Association Impairment Scale [AIS] A, B, or C) acquired at 24, 48, and 72 h post-injury. From a total of 165 proteins, we identified 27 potential biomarkers of injury severity (baseline AIS A, B, or C), with triosephosphate isomerase having the strongest relationship to AIS grade. The majority of affected proteins (24 of 27) were more abundant in samples from AIS A patients than in those from AIS C patients, suggesting that for the most part, these proteins are released into the CSF more readily with more severe trauma to the spinal cord. We then analyzed the relationship between CSF protein abundance and neurological recovery. For AIS grade improvement over 6 months, we identified 34 proteins that were associated with AIS grade conversion (p < 0.05); however, these associations were not statistically significant after adjusting for multiple comparisons. For total motor score (TMS) recovery over 6 months, after adjusting for baseline neurological injury level, we identified 46 proteins with a statistically significant association with TMS recovery. Twenty-two of these proteins were among the 27 proteins that were related to baseline AIS grade, consistent with the notion that protein markers that reflect a more severe injury also appropriately predict a poorer recovery of motor function. In summary, this study provides a description of the CSF proteome changes that occur after acute human SCI, and reveals a number of protein candidates for further validation as potential biomarkers of injury severity.

The optimization and maintenance of mean arterial blood pressure (MAP) and the general avoidance of systemic hypotension for the first 5-7 days following acute traumatic spinal cord injury (tSCI) is considered to be important for minimizing secondary spinal cord ischemic damage. The characterization of hemodynamic parameters in the immediate post-injury stage prior to admission to a specialized spine unit has not been previously reported. Here we describe the blood pressure management of 40 acute tSCI patients in the early post-injury phases of care prior to their arrival in a specialized spinal injury high dependency unit (HDU), intensive care unit (ICU), or operating room (OR). This study found that a significant proportion of these patients experience periods of relative hypotension prior to their admission to a specialized spinal unit. In particular, the mean calculated MAP was 78.8 mm Hg, with 52% of MAP measurements <80 mm Hg at primary receiving hospitals. Despite having a mean calculated MAP of 83.3 mm Hg in the emergency room of the tertiary hospital, 40% of the MAP measurements were <80 mm Hg. Although stringent monitoring and management of MAP may be facilitated and adhered to in a spinal HDU, ICU, or OR, it is important to recognize that acute traumatic SCI patients may experience many periods of relative hypotension prior to their arrival in such specialized units. This study highlights the need for education and awareness to optimize the hemodynamic management of acute SCI patients during the immediate post-injury period.

Traumatic spinal cord injury (SCI) represents a significant burden of illness, but it is relatively uncommon and heterogeneous, making it challenging to achieve sufficient subject enrollment in clinical trials of therapeutic interventions for acute SCI. The Rick Hansen Spinal Cord Injury Registry (RHSCIR) is a national SCI Registry that enters patients with SCI from acute-care centers across Canada. To predict the feasibility of conducting clinical trials of acute SCI within Canada, we have applied the inclusion/exclusion criteria of six previously conducted SCI trials to the RHSCIR data set and generated estimates of how many Canadian persons would have been eligible theoretically for enrollment in these studies. Data for SCI cases were prospectively collected for RHSCIR at 18 acute and 13 rehabilitation sites across Canada. RHSCIR patients enrolled between 2009-2013 who met the following key criteria were included: non-penetrating traumatic SCI; received acute care at a RHSCIR site; age more than 18, less than 75 years, and had complete admission single neurological level of injury data. Inclusion and exclusion criteria for the Minocycline in Acute Spinal Cord injury (Minocycline), Riluzole, Surgical Timing in Acute Spinal Cord Injury Study (STASCIS), Cethrin, Nogo antibody study (NOGO), and Sygen studies were applied retrospectively to this data set. The numbers of patients eligible for each clinical trial were determined. There were 2166 of the initial 2714 patients (79.8%) who met the key criteria and were included in the data set. Projected annual numbers of eligible patients for each trial were: Minocycline, 117; Riluzole, 62; STASCIS, 109; Cethrin, 101; NOGO, 82; and Sygen, 70. An additional 8.0% of the sample had a major head injury (Glasgow Coma Scale [GCS] score ≤12) and would have been excluded from the trials. RHSCIR provides a comprehensive national data set that may serve as a useful tool in the planning of multicenter clinical SCI trials.

Neurologic impairment after spinal cord injury (SCI) is currently measured and classified by functional examination. Biological markers that objectively classify injury severity and predict outcome would greatly facilitate efforts to evaluate acute SCI therapies. The purpose of this study was to determine how well inflammatory and structural proteins within the cerebrospinal fluid (CSF) of acute traumatic SCI patients predicted American Spinal Injury Association Impairment Scale (AIS) grade conversion and motor score improvement over 6 months. Fifty acute SCI patients (29 AIS A, 9 AIS B, 12 AIS C; 32 cervical, 18 thoracic) were enrolled and CSF obtained through lumbar intrathecal catheters to analyze interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, tau, S100β, and glial fibrillary acidic protein (GFAP) at 24 h post-injury. The levels of IL-6, tau, S100β, and GFAP were significantly different between patients with baseline AIS grades of A, B, or C. The levels of all proteins (IL-6, IL-8, MCP-1, tau, S100β, and GFAP) were significantly different between those who improved an AIS grade over 6 months and those who did not improve. Linear discriminant analysis modeling was 83% accurate in predicting AIS conversion. For AIS A patients, the concentrations of proteins such as IL-6 and S100β correlated with conversion to AIS B or C. Motor score improvement also was strongly correlated with the 24-h post-injury CSF levels of all six biomarkers. The analysis of CSF can provide valuable biological information about injury severity and recovery potential after acute SCI. Such biological markers may be valuable tools for stratifying individuals in acute clinical trials where variability in spontaneous recovery requires large recruitment cohorts for sufficient power.

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl 2 ) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO 4 ), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO 4 did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO 4 treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO 4 treatment. Finally, AC105 did not result in higher Mg 2+ levels in CSF than with the use of standard MgSO 4 . In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.

In the military environment, injured soldiers undergoing medical evacuation via helicopter or mine-resistant ambush-protected vehicle (MRAP) are subjected to vibration and shock inherent to the transport vehicle. We conducted the present study to assess the consequences of such vibration on the acutely injured spinal cord. We used a porcine model of spinal cord injury (SCI). After a T10 contusion-compression injury, animals were subjected to 1) no vibration (n = 7-8), 2) whole body vibration at frequencies and amplitudes simulating helicopter transport (n = 8), or 3) whole body vibration simulating ground transportation in an MRAP ambulance (n = 7). Hindlimb locomotor function (using Porcine Thoracic Injury Behavior Scale [PTIBS]), Eriochrome Cyanine histochemistry and biochemical analysis of inflammatory and neural damage markers were analyzed. Cerebrospinal fluid (CSF) expression levels for monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-8, and glial fibrillary acidic protein (GFAP) were similar between the helicopter or MRAP group and the unvibrated controls. Spared white/gray matter tended to be lower in the MRAP-vibrated animals than in the unvibrated controls, especially rostral to the epicenter. However, spared white/gray matter in the helicopter-vibrated group appeared normal. Although there was a relationship between the extent of sparing and the extent of locomotor recovery, no significant differences were found in PTIBS scores between the groups. In summary, exposures to vibration in the context of ground (MRAP) or aeromedical (helicopter) transportation did not significantly impair functional outcome in our large animal model of SCI. However, MRAP vibration was associated with increased tissue damage around the injury site, warranting caution around exposure to vehicle vibration acutely after SCI.

The objective of this study was to compare the long-term histological and behavioral outcomes after spinal cord injury (SCI) induced by one of three distinct biomechanical mechanisms: dislocation, contusion, and distraction. Thirty male Sprague-Dawley rats were randomized to incur a traumatic cervical SCI by one of these three clinically relevant mechanisms. The injured cervical spines were surgically stabilized, and motor function was assessed for the following 8 weeks. The spinal cords were then harvested for histologic analysis. Quantification of white matter sparing using Luxol fast blue staining revealed that dislocation injury caused the greatest overall loss of white matter, both laterally and along the rostrocaudal axis of the injured cord. Distraction caused enlarged extracellular spaces and structural alteration in the white matter but spared the most myelinated axons overall. Contusion caused the most severe loss of myelinated axons in the dorsal white matter. Immunohistochemistry for the neuronal marker NeuN combined with Fluoro Nissl revealed that the dislocation mechanism resulted in the greatest neuronal cell losses in both the ventral and dorsal horns. After the distraction injury mechanism, animals displayed no recovery of grip strength over time, in contrast to the animals subjected to contusion or dislocation injuries. After the dislocation injury mechanism, animals displayed no improvement in the grooming test, in contrast to the animals subjected to contusion or distraction injuries. These data indicate that different SCI mechanisms result in distinct patterns of histopathology and behavioral recovery. Understanding this heterogeneity may be important for the future development of therapeutic interventions that target specific neuropathology after SCI., Competing Interests: Author Disclosure Statement No competing financial interests exist.

In prior analyses of the effectiveness of methylprednisolone for the treatment of patients with acute traumatic spinal cord injuries (TSCIs), the prognostic importance of patients' neurological levels of injury and their baseline severity of impairment has not been considered. Our objective was to determine whether methylprednisolone improved motor recovery among participants in the Rick Hansen Spinal Cord Injury Registry (RHSCIR). We identified RHSCIR participants who received methylprednisolone according to the Second National Spinal Cord Injury Study (NASCIS-II) protocol and used propensity score matching to account for age, sex, time of neurological exam, varying neurological level of injury, and baseline severity of neurological impairment. We compared changes in total, upper extremity, and lower extremity motor scores using the Wilcoxon signed-rank test and performed sensitivity analyses using negative binomial regression. Forty-six patients received methylprednisolone and 1555 received no steroid treatment. There were no significant differences between matched participants for each of total (13.7 vs. 14.1, respectively; p=0.43), upper extremity (7.3 vs. 6.4; p=0.38), and lower extremity (6.5 vs. 7.7; p=0.40) motor recovery. This result was confirmed using a multivariate model and, as predicted, only cervical (C1-T1) rather than thoracolumbar (T2-L3) injury levels (p<0.01) and reduced baseline injury severity (American Spinal Injury Association [ASIA] Impairment Scale grades; p<0.01) were associated with greater motor score recovery. There was no in-hospital mortality in either group; however, the NASCIS-II methylprednisolone group had a significantly higher rate of total complications (61% vs. 36%; p=0.02) NASCIS-II methylprednisolone did not improve motor score recovery in RHSCIR patients with acute TSCIs in either the cervical or thoracic spine when the influence of anatomical level and severity of injury were included in the analysis. There was a significantly higher rate of total complications in the NASCIS-II methylprednisolone group. These findings support guideline recommendations against routine administration of methylprednisolone in acute TSCI.

Whole-body vibration has been identified as a potential stressor to spinal cord injury (SCI) patients during pre-hospital transportation. However, the effect that such vibration has on the acutely injured spinal cord is largely unknown, particularly in the frequency domain of 5 Hz in which resonance of the spine occurs. The objective of the study was to investigate the consequences of resonance vibration on the injured spinal cord. Using our previously characterized porcine model of SCI, we subjected animals to resonance vibration (5.7±0.46 Hz) or no vibration for a period of 1.5 or 3.0 h. Locomotor function was assessed weekly and cerebrospinal fluid (CSF) samples were collected to assess different inflammatory and injury severity markers. Spinal cords were evaluated histologically to quantify preserved white and gray matter. No significant differences were found between groups for CSF levels of monocyte chemotactic protein-1, interleukin 6 (IL-6) and lL-8. Glial fibrillary acidic protein levels were lower in the resonance vibration group, compared with the non-vibrated control group. Spared white matter tissue was increased within the vibrated group at 7 d post-injury but this difference was not apparent at the 12-week time-point. No significant difference was observed in locomotor recovery following resonance vibration of the spine. Here, we demonstrate that exposure to resonance vibration for 1.5 or 3 h following SCI in our porcine model is not detrimental to the functional or histological outcomes. Our observation that a 3.0-h period of vibration at resonance frequency induces modest histological improvement at one week post-injury warrants further study.

To determine the influence of time from injury to surgery on neurological recovery and length of stay (LOS) in an observational cohort of individuals with traumatic spinal cord injury (tSCI), we analyzed the baseline and follow-up motor scores of participants in the Rick Hansen Spinal Cord Injury Registry to specifically assess the effect of an early (less than 24 h from injury) surgical procedure on motor recovery and on LOS. One thousand four hundred and ten patients who sustained acute tSCIs with baseline American Spinal Injury Association Impairment Scale (AIS) grades A, B, C, or D and were treated surgically were analyzed to determine the effect of the timing of surgery (24, 48, or 72 h from injury) on motor recovery and LOS. Depending on the distribution of data, we used different types of generalized linear models, including multiple linear regression, gamma regression, and negative binomial regression. Persons with incomplete AIS B, C, and D injuries from C2 to L2 demonstrated motor recovery improvement of an additional 6.3 motor points (SE=2.8 p<0.03) when they underwent surgical treatment within 24 h from the time of injury, compared with those who had surgery later than 24 h post-injury. This beneficial effect of early surgery on motor recovery was not seen in the patients with AIS A complete SCI. AIS A and B patients who received early surgery experienced shorter hospital LOS. While the issues of when to perform surgery and what specific operation to perform remain controversial, this work provides evidence that for an incomplete acute tSCI in the cervical, thoracic, or thoracolumbar spine, surgery performed within 24 h from injury improves motor neurological recovery. Early surgery also reduces LOS.

Clinical trials of therapies for acute traumatic spinal cord injury (tSCI) have failed to convincingly demonstrate efficacy in improving neurologic function. Failing to acknowledge the heterogeneity of these injuries and under-appreciating the impact of the most important baseline prognostic variables likely contributes to this translational failure. Our hypothesis was that neurological level and severity of initial injury (measured by the American Spinal Injury Association Impairment Scale [AIS]) act jointly and are the major determinants of motor recovery. Our objective was to quantify the influence of these variables when considered together on early motor score recovery following acute tSCI. Eight hundred thirty-six participants from the Rick Hansen Spinal Cord Injury Registry were analyzed for motor score improvement from baseline to follow-up. In AIS A, B, and C patients, cervical and thoracic injuries displayed significantly different motor score recovery. AIS A patients with thoracic (T2-T10) and thoracolumbar (T11-L2) injuries had significantly different motor improvement. High (C1-C4) and low (C5-T1) cervical injuries demonstrated differences in upper extremity motor recovery in AIS B, C, and D. A hypothetical clinical trial example demonstrated the benefits of stratifying on neurological level and severity of injury. Clinically meaningful motor score recovery is predictably related to the neurological level of injury and the severity of the baseline neurological impairment. Stratifying clinical trial cohorts using a joint distribution of these two variables will enhance a study's chance of identifying a true treatment effect and minimize the risk of misattributed treatment effects. Clinical studies should stratify participants based on these factors and record the number of participants and their mean baseline motor scores for each category of this joint distribution as part of the reporting of participant characteristics. Improved clinical trial design is a high priority as new therapies and interventions for tSCI emerge.

In animal models, spinal cord injury (SCI) is typically imparted by contusion alone (e.g., weight drop) or by compression alone (e.g., clip compression). In humans, however, the cord is typically injured by a combination of violent contusion followed by varying degrees of ongoing mechanical compression. Understanding how the combination of contusion and compression influences the early pathophysiology of SCI is important for the pre-clinical development of neuroprotective therapies that are applicable to the human condition. Disturbances in the metabolism of energy-related substrates such as lactate, pyruvate, and glucose are important aspects of secondary damage. In this study, we used a porcine model of traumatic SCI to determine the extent to which these metabolites were influenced by contusion followed by sustained compression, using the microdialysis technique. Following contusion injury, lactate and pyruvate levels near the epicenter both increased, while glucose remained quite stable. When the contusion injury was followed by sustained compression, we observed a transient rise in lactate, while pyruvate and glucose levels dropped rapidly, which may reflect decreased regional spinal cord blood flow. Furthermore, contusion with sustained compression produced a prolonged and dramatic increase in the lactate-pyruvate (L/P) ratio as a marker of tissue hypoxia, whereas after contusion injury alone, a transient and less significant elevation of the L/P ratio was observed. In this study, we demonstrate that disturbances in energy metabolism within the injured spinal cord vary greatly depending upon the biomechanical nature of the injury. Such differences are likely to be relevant to the applicability of novel therapies targeting specific aspects of the early secondary injury cascade after acute human SCI.

Spinal cord injuries are frequently accompanied by persisting residual compression of the spinal cord; however, it remains controversial as to what effect the sustained compression has on neurological damage. The objective of this study was to determine the influence of post-traumatic residual spinal cord compression on the extent and progression of tissue damage within a dynamic thoracic contusion rat model. Twenty-nine male Wistar rats were distributed into one of four groups: spinal cord contusion only, contusion with 40% residual compression, contusion with 90% residual compression, and a surgical control group. A moderate injury was performed (1 mm, 700 mm/sec) with our custom University of British Columbia (UBC) multimechanism apparatus, and the residual compression groups had the impactor tip maintained at 40% or 90% of the initial impact depth (1.0 mm) for 60 min post-injury. All animals were killed at 3 h post-injury, when the spinal cord was harvested and stained for hemorrhage, neuronal damage in the gray matter, and axonal disruption in the white matter. The initial contusion injury immediately damaged tissue beneath the impactor as evidenced by rapid relaxation of the reaction force on the spinal cord during the subsequent compression. Importantly, the rostral-caudal extent of intramedullary hemorrhage was 66% larger after 90% residual spinal cord compression compared to the 40% group (p=0.016). Similarly, the extent of neuronal nuclei lost in different gray matter regions was 60-86% greater after 90% residual compression compared with 40% (p<0.001). Thus, a high level of residual compression of the spinal cord following a moderate contusion injury has the potential to adversely increase the extent of tissue damage, whereas a lower level of residual compression may have little to no effect.

The majority of clinical spinal cord injuries (SCIs) are contusive and occur at the cervical level of the spinal cord. Most scientists and clinicians agree that the preclinical evaluation of novel candidate treatments should include testing in a cervical SCI contusion model. Because mice are increasingly used because of the availability of genetically engineered lines, we characterized a novel cervical hemicontusion injury in mice using the Infinite Horizon Spinal Cord Impactor (Precisions Systems & Instrumentation, Lexington, KY). In the current study, C57BL/6 mice received a hemicontusion injury of 75 kilodynes with or without dwell time in an attempt to elicit a sustained moderate-to-severe motor deficit. Hemicontusion injuries without dwell time resulted in sustained deficits of the affected forepaw, as revealed by a 3-fold decrease in usage during rearing, a ∼50% reduction in grooming scores, and retrieval of significantly fewer pellets on the Montoya staircase test. Only minor transient deficits were observed in grasping force. CatWalk analysis revealed reduced paw-print size and swing speed of the affected forelimb. Added dwell time of 15 or 30 sec significantly worsened behavioral outcome, and mice demonstrated minimal ability of grasping, paw usage, and overground locomotion. Besides worsening of behavioral deficits, added dwell time also reduced residual white and gray matter at the epicenter and rostral-caudal to the injury, including on the contralateral side of the spinal cord. Taken together, we developed and characterized a new hemicontusion SCI model in mice that produces sufficient and sustained impairments in gross and skilled forelimb function and produced primarily unilateral functional deficits.