Pharmacologic and Nonpharmacologic Treatment Modalities for Bone Loss in SCI - Proposal for Combined Approach.

Increased risk of bone fracture due to bone mineral density (BMD) loss is a serious consequence of spinal cord injury (SCI). Traditionally, pharmaceutical approaches, such as bisphosphonates, have been prescribed to prevent bone loss. However, there is controversy in the literature regarding efficacy of these medications to mitigate the drastic bone loss following SCI. Individuals with SCI are particularly at risk of osteoporosis because of the lack of ambulation and weight bearing activities. In the past two decades, functional electric stimulation (FES) has allowed for another approach to treat bone loss. FES approaches are expanding into various modalities such as cycling and rowing exercises and show promising outcomes with minimal consequences. In addition, these non-pharmacological treatments can elevate overall physical and mental health. This article provides an overview of efficacy of different treatment options for BMD loss for SCI and advocates for a combined approach be pursued in standard of care.

Epidural stimulation restores muscle synergies by modulating neural drives in participants with sensorimotor complete spinal cord injuries.

Multiple studies have corroborated the restoration of volitional motor control after motor-complete spinal cord injury (SCI) through the use of epidural spinal cord stimulation (eSCS), but rigorous quantitative descriptions of muscle coordination have been lacking. Six participants with chronic, motor and sensory complete SCI underwent a brain motor control assessment (BMCA) consisting of a set of structured motor tasks with and without eSCS. We investigated how muscle activity complexity and muscle synergies changed with and without stimulation. We performed this analysis to better characterize the impact of stimulation on neuromuscular control. We also recorded data from nine healthy participants as controls. Competition exists between the task origin and neural origin hypotheses underlying muscle synergies. The ability to restore motor control with eSCS in participants with motor and sensory complete SCI allows us to test whether changes in muscle synergies reflect a neural basis in the same task. Muscle activity complexity was computed with Higuchi Fractal Dimensional (HFD) analysis, and muscle synergies were estimated using non-negative matrix factorization (NNMF) in six participants with American Spinal Injury Association (ASIA) Impairment Score (AIS) A. We found that the complexity of muscle activity was immediately reduced by eSCS in the SCI participants. We also found that over the follow-up sessions, the muscle synergy structure of the SCI participants became more defined, and the number of synergies decreased over time, indicating improved coordination between muscle groups. Lastly, we found that the muscle synergies were restored with eSCS, supporting the neural hypothesis of muscle synergies. We conclude that eSCS restores muscle movements and muscle synergies that are distinct from those of healthy, able-bodied controls.

Mapping Spinal Cord Stimulation-Evoked Muscle Responses in Patients With Chronic Spinal Cord Injury.

OBJECTIVES: Epidural spinal cord stimulation (eSCS) has shown promise for restoring some volitional motor control after spinal cord injury (SCI). Maximizing therapeutic response requires effective spatial stimulation generated through careful configuration of anodes and cathodes on the eSCS lead. By exploring the way the spatial distribution of low frequency stimulation affects muscle activation patterns, we investigated the spatial specificity of stimulation-evoked responses for targeted muscle groups for restoration after chronic SCI (cSCI) in participants in the Epidural Stimulation After Neurologic Damage (E-STAND) trial. MATERIALS AND METHODS: Fifteen participants with Abbreviated Injury Scale A cSCI from the E-STAND study were evaluated with a wide range of bipolar spatial patterns. Surface electromyography captured stimulation-evoked responses from the rectus abdominis (RA), intercostal, paraspinal, iliopsoas, rectus femoris (RF), tibialis anterior (TA), extensor hallucis longus (EHL), and gastrocnemius muscle groups bilaterally. Peak-to-peak amplitudes were analyzed for each pulse across muscles. Stimulation patterns with dipoles parallel (vertical configurations), perpendicular (horizontal configurations), and oblique (diagonal configurations) relative to the rostral-caudal axis were evaluated. RESULTS: Cathodic stimulation in the transverse plane indicated ipsilaterally biased activation in RA, intercostal, paraspinal, iliopsoas, RF, TA, EHL, and gastrocnemius muscles (p < 0.05). We found that caudal cathodic stimulation was significantly more activating only in the RF and EHL muscle groups than in the rostral (p < 0.037 and p < 0.006, respectively). Oblique stimulation was found to be more activating in the RA, intercostal, paraspinal, iliopsoas, and TA muscle groups than in the transverse (p < 0.05). CONCLUSIONS: Cathodic stimulation provides uniform specificity for targeting laterality. Few muscle groups responded specifically to variation in rostral/caudal stimulation, and oblique stimulation improved stimulation responses when compared with horizontal configurations. These relations may enable tailored targeting of muscle groups, but the surprising amount of variation observed suggests that monitoring these evoked muscle responses will play a key role in this tailoring process. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03026816.

Human induced pluripotent stem cells integrate, create synapses and extend long axons after spinal cord injury.

Numerous interventions have been explored in animal models using cells differentiated from human induced pluripotent stem cells (iPSCs) in the context of neural injury with some success. Our work seeks to transplant cells that are generated from hiPSCs into regionally specific spinal neural progenitor cells (sNPCs) utilizing a novel accelerated differentiation protocol designed for clinical translation. We chose a xenotransplantation model because our laboratory is focused on the behaviour of human cells in order to bring this potential therapy to translation. Cells were transplanted into adult immunodeficient rats after moderate contusion spinal cord injury (SCI). Twelve weeks later, cells derived from the transplanted sNPCs survived and differentiated into neurons and glia that filled the lesion cavity and produced a thoracic spinal cord transcriptional program in vivo. Furthermore, neurogenesis and ionic channel expression were promoted within the adjacent host spinal cord tissue. Transplanted cells displayed robust integration properties including synapse formation and myelination by host oligodendrocytes. Axons from transplanted hiPSC sNPC-derived cells extended both rostrally and caudally from the SCI transplant site, rostrally approximately 6 cm into supraspinal structures. Thus, iPSC-derived sNPCs may provide a patient-specific cell source for patients with SCI that could provide a relay system across the site of injury.

The safety of epidural spinal cord stimulation to restore function after spinal cord injury: post-surgical complications and incidence of cardiovascular events.

STUDY DESIGN: Cohort prospective study. OBJECTIVES: Epidural spinal cord stimulation (eSCS) improves volitional motor and autonomic function after spinal cord injury (SCI). While eSCS has an established history of safety for chronic pain, it remains unclear if eSCS in the SCI population presents the same risk profile. We aimed to assess safety and autonomic monitoring data for the first 14 participants in the E-STAND trial. SETTING: Hennepin County Medical Center, Minneapolis and Minneapolis Veterans Affairs Medical Center, Minnesota, USA. METHODS: Monthly follow-up visits assessed surgical and medical device-related safety outcomes as well as stimulation usage. Beat-by-beat blood pressure (BP) and continuous electrocardiogram data were collected during head-up tilt-table testing with and without eSCS. RESULTS: All participants had a motor-complete SCI. Mean (SD) age and time since injury were 38 (10) and 7 (5) years, respectively. There were no surgical complications but one device malfunction 4 months post implantation. Stimulation was applied for up to 23 h/day, across a broad range of parameters: frequency (18-700 Hz), pulse width (100-600 µs), and amplitude (0.4-17 mA), with no adverse events reported. Tilt-table testing with eSCS demonstrated no significant increases in the incidence of elevated systolic BP or a greater frequency of arrhythmias. CONCLUSIONS: eSCS to restore autonomic and volitional motor function following SCI has a similar safety profile as when used to treat chronic pain, despite the prevalence of significant comorbidities and the wide variety of stimulation parameters tested.

Accelerated differentiation of human pluripotent stem cells into neural lineages via an early intermediate ectoderm population.

Differentiation of human pluripotent stem cells (hPSCs) into ectoderm provides neurons and glia useful for research, disease modeling, drug discovery, and potential cell therapies. In current protocols, hPSCs are traditionally differentiated into an obligate rostro-dorsal ectodermal fate expressing PAX6 after 6 to 12 days in vitro when protected from mesendoderm inducers. This rate-limiting step has performed a long-standing role in hindering the development of rapid differentiation protocols for ectoderm-derived cell types, as any protocol requires 6 to 10 days in vitro to simply initiate. Here, we report efficient differentiation of hPSCs into a naive early ectodermal intermediate within 24 hours using combined inhibition of bone morphogenic protein and fibroblast growth factor signaling. The induced population responds immediately to morphogen gradients to upregulate rostro-caudal neurodevelopmental landmark gene expression in a generally accelerated fashion. This method can serve as a new platform for the development of novel, rapid, and efficient protocols for the manufacture of hPSC-derived neural lineages.

3D Printed Neural Regeneration Devices.

Neural regeneration devices interface with the nervous system and can provide flexibility in material choice, implantation without the need for additional surgeries, and the ability to serve as guides augmented with physical, biological (e.g., cellular), and biochemical functionalities. Given the complexity and challenges associated with neural regeneration, a 3D printing approach to the design and manufacturing of neural devices could provide next-generation opportunities for advanced neural regeneration via the production of anatomically accurate geometries, spatial distributions of cellular components, and incorporation of therapeutic biomolecules. A 3D printing-based approach offers compatibility with 3D scanning, computer modeling, choice of input material, and increasing control over hierarchical integration. Therefore, a 3D printed implantable platform could ultimately be used to prepare novel biomimetic scaffolds and model complex tissue architectures for clinical implants in order to treat neurological diseases and injuries. Further, the flexibility and specificity offered by 3D printed in vitro platforms have the potential to be a significant foundational breakthrough with broad research implications in cell signaling and drug screening for personalized healthcare. This progress report examines recent advances in 3D printing strategies for neural regeneration as well as insight into how these approaches can be improved in future studies.

Examining the Emergency Medical Treatment and Active Labor Act: impact on telemedicine for neurotrauma.

The Emergency Medical Treatment and Active Labor Act (EMTALA) protects patient access to emergency medical treatment regardless of insurance or socioeconomic status. A significant result of the COVID-19 pandemic has been the rapid acceleration in the adoption of telemedicine services across many facets of healthcare. However, very little literature exists regarding the use of telemedicine in the context of EMTALA. This work aimed to evaluate the potential to expand the usage of telemedicine services for neurotrauma to reduce transfer rates, minimize movement of patients across borders, and alleviate the burden on tertiary care hospitals involved in the care of patients with COVID-19 during a global pandemic. In this paper, the authors outline EMTALA provisions, provide examples of EMTALA violations involving neurosurgical care, and propose guidelines for the creation of telemedicine protocols between referring and consulting institutions.

3D Printed Stem-Cell Derived Neural Progenitors Generate Spinal Cord Scaffolds.

A bioengineered spinal cord is fabricated via extrusion-based multi-material 3D bioprinting, in which clusters of induced pluripotent stem cell (iPSC)-derived spinal neuronal progenitor cells (sNPCs) and oligodendrocyte progenitor cells (OPCs) are placed in precise positions within 3D printed biocompatible scaffolds during assembly. The location of a cluster of cells, of a single type or multiple types, is controlled using a point-dispensing printing method with a 200 µm center-to-center spacing within 150 µm wide channels. The bioprinted sNPCs differentiate and extend axons throughout microscale scaffold channels, and the activity of these neuronal networks is confirmed by physiological spontaneous calcium flux studies. Successful bioprinting of OPCs in combination with sNPCs demonstrates a multicellular neural tissue engineering approach, where the ability to direct the patterning and combination of transplanted neuronal and glial cells can be beneficial in rebuilding functional axonal connections across areas of central nervous system (CNS) tissue damage. This platform can be used to prepare novel biomimetic, hydrogel-based scaffolds modeling complex CNS tissue architecture in vitro and harnessed to develop new clinical approaches to treat neurological diseases, including spinal cord injury.

T cell deficiency in spinal cord injury: altered locomotor recovery and whole-genome transcriptional analysis.

BACKGROUND: T cells undergo autoimmunization following spinal cord injury (SCI) and play both protective and destructive roles during the recovery process. T cell-deficient athymic nude (AN) rats exhibit improved functional recovery when compared to immunocompetent Sprague-Dawley (SD) rats following spinal cord transection. METHODS: In the present study, we evaluated locomotor recovery in SD and AN rats following moderate spinal cord contusion. To explain variable locomotor outcome, we assessed whole-genome expression using RNA sequencing, in the acute (1 week post-injury) and chronic (8 weeks post-injury) phases of recovery. RESULTS: Athymic nude rats demonstrated greater locomotor function than SD rats only at 1 week post-injury, coinciding with peak T cell infiltration in immunocompetent rats. Genetic markers for T cells and helper T cells were acutely enriched in SD rats, while AN rats expressed genes for T(h)2 cells, cytotoxic T cells, NK cells, mast cells, IL-1a, and IL-6 at higher levels. Acute enrichment of cell death-related genes suggested that SD rats undergo secondary tissue damage from T cells. Additionally, SD rats exhibited increased acute expression of voltage-gated potassium (Kv) channel-related genes. However, AN rats demonstrated greater chronic expression of cell death-associated genes and less expression of axon-related genes. Immunostaining for macrophage markers revealed no T cell-dependent difference in the acute macrophage infiltrate. CONCLUSIONS: We put forth a model in which T cells facilitate early tissue damage, demyelination, and Kv channel dysregulation in SD rats following contusion SCI. However, compensatory features of the immune response in AN rats cause delayed tissue death and limit long-term recovery. T cell inhibition combined with other neuroprotective treatment may thus be a promising therapeutic avenue.

Cell Transplantation for Repair of the Spinal Cord and Prospects for Generating Region-Specific Exogenic Neuronal Cells.

Spinal cord injury (SCI) is associated with currently irreversible consequences in several functional components of the central nervous system. Despite the severity of injury, there remains no approved treatment to restore function. However, with a growing number of preclinical studies and clinical trials, cell transplantation has gained significant potential as a treatment for SCI. Researchers have identified several cell types as potential candidates for transplantation. To optimize successful functional outcomes after transplantation, one key factor concerns generating neuronal cells with regional and subtype specificity, thus calling on the developmental transcriptome patterning of spinal cord cells. A potential source of spinal cord cells for transplantation is the generation of exogenic neuronal progenitor cells via the emerging technologies of gene editing and blastocyst complementation. This review highlights the use of cell transplantation to treat SCI in the context of relevant developmental gene expression patterns useful for producing regionally specific exogenic spinal cells via in vitro differentiation and blastocyst complementation.

Sagittal balance in sitting and standing positions: A systematic review of radiographic measures.

Background: Sagittal imbalance can be caused by various etiologies and is among the most important indicators of spinal deformity. Sagittal balance can be restored through surgical intervention based on several radiographic measures. The purpose of this study is to review the normal parameters in the sitting position, which are not well understood and could have significant implications for non-ambulatory patients. Methods: A systematic review was performed adhering to PRISMA Guidelines. Using R-software, the weighted means and 95% confidence intervals of the radiographic findings were calculated using a random effect model and significance testing using unpaired t-tests. Results: 10 articles with a total of 1066 subjects reported radiographic measures of subjects with no spinal deformity in the sitting and standing position. In the healthy individual, standing sagittal vertical axis -16.8°was significantly less than sitting 28.4° (p < 0.0001), while standing lumbar lordosis 43.3°is significantly greater than sitting 21.3° (p < 0.0001). Thoracic kyphosis was not significantly different between the two groups (p = 0.368). Standing sacral slope 34.3° was significantly greater than sitting 19.5° (p < 0.0001) and standing pelvic tilt 14.0° was significantly less than sitting 33.9° (p < 0.0001). Conclusions: There are key differences between standing and sitting postures, which could lead to undue stress on surgical implants and poor outcomes, especially for non-ambulatory populations. There is a need for more studies reporting sitting and standing radiographic measures in different postures and spinal conditions.

Utilization of Locum Tenens in Neurosurgery.

INTRODUCTION: Despite its rising popularity, little has been described about locum tenens employment (locums) in neurosurgery. This study provides the first nationwide overview of the locums neurosurgery experience. METHODS: An anonymous online survey examined practice characteristics of respondents, extent of and satisfaction with locums, motivations for pursuing locums, case volumes, agencies used, compensation, and positive/negative aspects of experiences. Responses were collected between November 2020 and February 2021. RESULTS: Response rate for the 1852 neurosurgeons who opened the survey request was 4.9%; 36 of 91 respondents had previously worked locums and were commonly motivated by compensation or transitioning to new jobs or retirement. In our response group, 92% of locums respondents had taken more than one position and 47% had taken more than 10. Neurosurgeons performing <200 cases/year were significantly more likely to have also worked locums than those performing >200 cases/year (41.6% locums, 12.7% non-locums, P = 0.001). Responses showed that 69% of locums respondents earned $2000-$2999/day and 16% earned >$3500/day. Nearly 78% of locums respondents were satisfied with their experience(s) and 86% would take another future locums position. Being in practice for >15 years was significantly associated with satisfaction with locums (P = 0.03). Reported flaws included unfamiliarity with hospitals, limited continuity of care, credentialing burdens, and inadequate travel compensation. CONCLUSIONS: Locums is utilized by neurosurgeons across multiple practice types and may serve to complement workloads or "fill in gaps" between longer-term employment. Overall, locums neurosurgeons are well compensated, and the majority are satisfied with their experience(s). Inevitably, flaws still exist with locums employment, which may be the focus of organized efforts aiming to improve the experience.

Accelerated differentiation of human induced pluripotent stem cells into regionally specific dorsal and ventral spinal neural progenitor cells for application in spinal cord therapeutics.

Spinal cord injury can attenuate both motor and sensory function with minimal potential for full recovery. Research utilizing human induced pluripotent stem cell (hiPSC) -derived spinal cell types for in vivo remodeling and neuromodulation after spinal cord injury has grown substantially in recent years. However, the majority of protocols for the differentiation of spinal neurons are lengthy, lack the appropriate dorsoventral or rostrocaudal specification, and are not typically replicated in more than one cell line. Furthermore, most researchers currently utilize hiPSC-derived motor neurons for cell transplantation after injury, with very little exploration of spinal sensory neuron transplantation. The lack of studies that utilize sensory populations may be due in part to the relative scarcity of dorsal horn differentiation protocols. Building upon our previously published work that demonstrated the rapid establishment of a primitive ectoderm population from hiPSCs, we describe here the production of a diverse population of both ventral spinal and dorsal horn progenitor cells. Our work creates a novel system allowing dorsal and ventral spinal neurons to be differentiated from the same intermediate ectoderm population, making it possible to construct the dorsal and ventral domains of the spinal cord while decreasing variability. This technology can be used in tandem with biomaterials and pharmacology to improve cell transplantation for spinal cord injury, increasing the potential for neuroregeneration.

Projected timeline to achieve gender balance within the United States neurosurgical workforce exceeds 150 years: a National Plan and Provider Enumeration System analysis.

OBJECTIVE: Despite incremental progress in the representation and proportion of women in the field of neurosurgery, female neurosurgeons still represent an overwhelming minority of the current US physician workforce. Prior research has predicted the timeline by which the proportion of female neurosurgery residents may reach that of males, but none have used the contemporary data involving the entire US neurosurgical workforce. METHODS: The authors performed a retrospective analysis of the National Plan and Provider Enumeration System (NPPES) registry of all US neurosurgeons to determine changes in the proportions of women in neurosurgery across states, census divisions, and census regions between 2010 and 2020. A univariate linear regression was performed to assess historical growth, and then Holt-Winter forecasting was used to predict in what future year gender parity may be reached in this field. RESULTS: A majority of states, divisions, and regions have increased the proportion of female neurosurgeons from 2010. Given current growth rates, the authors found that female neurosurgeons will not reach the proportion of women in the overall medical workforce until 2177 (95% CI 2169-2186). Furthermore, they found that women in neurosurgery will not match their current proportion of the overall US population until 2267 (95% CI 2256-2279). CONCLUSIONS: Whereas many studies have focused on the overall increase of women in neurosurgery in the last decade, this one is the first to compare this growth in the context of the overall female physician workforce and the female US population. The results suggest a longer timeline for gender parity in neurosurgery than previous studies have suggested and should further catalyze the targeted recruitment of women into the field, an overhaul of current policies in place to support and develop the careers of women in neurosurgery, and increased self-reflection and behavioral change from the entire neurosurgery community.

Neuromodulation Through Spinal Cord Stimulation Restores Ability to Voluntarily Cycle After Motor Complete Paraplegia.

Abstract Epidural spinal cord stimulation (eSCS) of the lower thoracic spinal cord has been shown to partially restore volitional movement in patients with complete chronic spinal cord injury (cSCI). Combining eSCS with intensive locomotor training improves motor function, including standing and stepping, but many patients with cSCI suffer from long-standing muscle atrophy and loss of bone mineral density, which may prohibit safe implementation. Safe, accessible, and effective avenues for pairing neuromodulation with activity-based therapy remain unexplored. Cycling is one such option that can be utilized as an eSCS therapy given its low-risk and low-weight-bearing requirement. We investigated the feasibility and kinematics of motor-assisted and passive cycle-based therapy for cSCI patients with epidural spinal cord stimulation. Seven participants who underwent spinal cord stimulation surgery in the Epidural Stimulation After Neurologic Damage (E-STAND) trial (NCT03026816) participated in a cycling task using the motor assist MOTOmed Muvi 300. A factorial design was used such that participants were asked to cycle with and without conscious effort with and without stimulation. We used mixed effects models assessing maximum power output and time pedaling unassisted to evaluate the interaction between stimulation and conscious effort. Cycling was well-tolerated and we observed no adverse events, including in participants up to 17 years post-initial injury and up to 58 years old. All participants were found to be able to pedal without motor assist, which primarily occurred when stimulation and effort were applied together (p = 0.001). Additionally, the combination of stimulation and intention was significantly associated with higher maximum power production (p < 0.0001) and distance pedaled (p = 0.0001). No association was found between volitional movement and participant factors: age, time since injury, and spinal cord atrophy. With stimulation and conscious effort, all participants were able to achieve active cycling without motor assistance. Thus, our stationary cycling factorial study design demonstrated volitional movement restoration with eSCS in a diverse study population of cSCI participants. Further, motor-assist cycling was well-tolerated without any adverse events. Cycling has the potential to be a safe research assessment and physical therapy modality for cSCI patients utilizing eSCS who have a high risk of injury with weight bearing exercise. The cycling modality in this study was demonstrated to be a straightforward assessment of motor function and safe for all participants regardless of age or time since initial injury.

Effect of epidural spinal cord stimulation on female sexual function after spinal cord injury.

Sexual dysfunction is a common consequence for women with spinal cord injury (SCI); however, current treatments are ineffective, especially in the under-prioritized population of women with SCI. This case-series, a secondary analysis of the Epidural Stimulation After Neurologic Damage (E-STAND) clinical trial aimed to investigate the effect of epidural spinal cord stimulation (ESCS) on sexual function and distress in women with SCI. Three females, with chronic, thoracic, sensorimotor complete SCI received daily (24 h/day) tonic ESCS for 13 months. Questionnaires, including the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS) were collected monthly. There was a 3.2-point (13.2%) mean increase in total FSFI from baseline (24.5 ± 4.1) to post-intervention (27.8 ± 6.6), with a 4.8-50% improvement in the sub-domains of desire, arousal, orgasm and satisfaction. Sexual distress was reduced by 55%, with a mean decrease of 12 points (55.4%) from baseline (21.7 ± 17.2) to post-intervention (9.7 ± 10.8). There was a clinically meaningful change of 14 points in the International Standards for Neurological Classification of Spinal Cord Injury total sensory score from baseline (102 ± 10.5) to post-intervention (116 ± 17.4), without aggravating dyspareunia. ESCS is a promising treatment for sexual dysfunction and distress in women with severe SCI. Developing therapeutic interventions for sexual function is one of the most meaningful recovery targets for people with SCI. Additional large-scale investigations are needed to understand the long-term safety and feasibility of ESCS as a viable therapy for sexual dysfunction. Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03026816, NCT03026816.

Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury.

BACKGROUND: There are currently no effective clinical therapies to ameliorate the loss of function that occurs after spinal cord injury. Electrical stimulation of the rat spinal cord through the rat tail has previously been described by our laboratory. We propose combinatorial treatment with human induced pluripotent stem cell-derived spinal neural progenitor cells (sNPCs) along with tail nerve electrical stimulation (TANES). The purpose of this study was to examine the influence of TANES on the differentiation of sNPCs with the hypothesis that the addition of TANES would affect incorporation of sNPCs into the injured spinal cord, which is our ultimate goal. METHODS: Chronically injured athymic nude rats were allocated to one of three treatment groups: injury only, sNPC only, or sNPC + TANES. Rats were sacrificed at 16 weeks post-transplantation, and tissue was processed and analyzed utilizing standard histological and tissue clearing techniques. Functional testing was performed. All quantitative data were presented as mean ± standard error of the mean. Statistics were conducted using GraphPad Prism. RESULTS: We found that sNPCs were multi-potent and retained the ability to differentiate into mainly neurons or oligodendrocytes after this transplantation paradigm. The addition of TANES resulted in more transplanted cells differentiating into oligodendrocytes compared with no TANES treatment, and more myelin was found. TANES not only promoted significantly higher numbers of sNPCs migrating away from the site of injection but also influenced long-distance axonal/dendritic projections especially in the rostral direction. Further, we observed localization of synaptophysin on SC121-positive cells, suggesting integration with host or surrounding neurons, and this finding was enhanced when TANES was applied. Also, rats that were transplanted with sNPCs in combination with TANES resulted in an increase in serotonergic fibers in the lumbar region. This suggests that TANES contributes to integration of sNPCs, as well as activity-dependent oligodendrocyte and myelin remodeling of the chronically injured spinal cord. CONCLUSIONS: Together, the data suggest that the added electrical stimulation promoted cellular integration and influenced the fate of human induced pluripotent stem cell-derived sNPCs transplanted into the injured spinal cord.

Changes in patterns of traumatic brain injury in the Michigan Trauma Quality Improvement Program database early in the COVID-19 pandemic.

OBJECTIVE: The authors' objective was to investigate the impact of the global COVID-19 pandemic on hospital presentation and process of care for the treatment of traumatic brain injuries (TBIs). Improved understanding of these effects will inform sociopolitical and hospital policies in response to future pandemics. METHODS: The Michigan Trauma Quality Improvement Program (MTQIP) database, which contains data from 36 level I and II trauma centers in Michigan and Minnesota, was queried to identify patients who sustained TBI on the basis of head/neck Abbreviated Injury Scale (AIS) codes during the periods of March 13 through July 2 of 2017-2019 (pre-COVID-19 period) and March 13, 2020, through July 2, 2020 (COVID-19 period). Analyses were performed to detect differences in incidence, patient characteristics, injury severity, and outcomes. RESULTS: There was an 18% decrease in the rate of encounters with TBI in the first 8 weeks (March 13 through May 7), followed by a 16% increase during the last 8 weeks (May 8 through July 2), of our COVID-19 period compared with the pre-COVID-19 period. Cumulatively, there was no difference in the rates of encounters with TBI between the COVID-19 and pre-COVID-19 periods. Severity of TBI, as measured with maximum AIS score for the head/neck region and Glasgow Coma Scale score, was also similar between periods. During the COVID-19 period, a greater proportion of patients with TBI presented more than a day after sustaining their injuries (p = 0.046). COVID-19 was also associated with a doubling in the decubitus ulcer rate from 1.0% to 2.1% (p = 0.002) and change in the distribution of discharge status (p = 0.01). Multivariable analysis showed no differences in odds of death/hospice discharge, intensive care unit stay of at least a day, or need for a ventilator for at least a day between the COVID-19 and pre-COVID-19 periods. CONCLUSIONS: During the early months of the COVID-19 pandemic, the number of patients who presented with TBI was initially lower than in the years 2017-2019 prior to the pandemic. However, there was a subsequent increase in the rate of encounters with TBI, resulting in overall similar rates of TBI between March 13 through July 2 during the COVID-19 period and during the pre-COVID-19 period. The COVID-19 cohort was also associated with negative impacts on time to presentation, rate of decubitus ulcers, and discharge with supervision. Policies in response to future pandemics must consider the resources necessary to care for patients with TBI.

Advances in Epidural Spinal Cord Stimulation to Restore Function after Spinal Cord Injury: History and Systematic Review.

Epidural spinal cord stimulation (eSCS) has been recently recognized as a potential therapy for chronic spinal cord injury (SCI). eSCS has been shown to uncover residual pathways within the damaged spinal cord. The purpose of this review is to summarize the key findings to date regarding the use of eSCS in SCI. Searches were carried out using MEDLINE, EMBASE, and Web of Science database and reference lists of the included articles. A combination of medical subject heading terms and keywords was used to find studies investigating the use of eSCS in SCI patients to facilitate volitional movement and to restore autonomic function. The risk of bias was assessed using Risk Of Bias In Non-Randomized Studies of Interventions tool for nonrandomized studies. We were able to include 40 articles that met our eligibility criteria. The studies included a total of 184 patient experiences with incomplete or complete SCI. The majority of the studies used the Medtronic 16 paddle lead. Around half of the studies reported lead placement between T11- L1. We included studies that assessed motor (n = 28), autonomic (n = 13), and other outcomes (n = 10). The majority of the studies reported improvement in outcomes assessed. The wide range of included outcomes demonstrates the effectiveness of eSCS in treating a diverse SCI population. However, the current studies cannot definitively conclude which patients benefit the most from this intervention. Further study in this area is needed to allow improvement of the eSCS technology and allow it to be more widely available for chronic SCI patients.