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OBJECTIVE Schwann cells (SCs) have been shown to play an essential role in axon regeneration in both peripheral nerve injuries (PNIs) and spinal cord injuries (SCIs). The transplantation of SCs as an adjunctive therapy is currently under investigation in human clinical trials due to their regenerative capacity. Therefore, a reliable method for procuring large quantities of SCs from peripheral nerves is necessary. This paper presents a well-developed, validated, and optimized manufacturing protocol for clinical-grade SCs that are compliant with Current Good Manufacturing Practices (CGMPs). METHODS The authors evaluated the SC culture manufacturing data from 18 clinical trial participants who were recruited for autologous SC transplantation due to subacute SCI (n = 7), chronic SCI (n = 8), or PNIs (n = 3). To initiate autologous SC cultures, a mean nerve length of 11.8 ± 3.7 cm was harvested either from the sural nerve alone (n = 17) or with the sciatic nerve (n = 1). The nerves were digested with enzymes and SCs were isolated and further expanded in multiple passages to meet the dose requirements for transplantation. RESULTS An average yield of 87.2 ± 89.2 million cells at P2 and 150.9 ± 129.9 million cells at P3 with high viability and purity was produced. Cell counts and rates of expansion increased with each subsequent passage from P0 to P3, with the largest rate of expansion between P2 and P3. Larger harvest nerve lengths correlated significantly with greater yields at P0 and P1 (p < 0.05). In addition, a viability and purity above 90% was sustained throughout all passages in nearly all cell products. CONCLUSIONS This study presents reliable CGMP-compliant manufacturing methods for autologous SC products that are suitable for regenerative treatment of patients with SCI, PNI, or other conditions.

Purpose of review Partnerships across all stakeholders in the research process strengthen the outcomes and ultimate usability of research. The purpose of this review is to discuss the current level of inclusion of people living with spinal cord injury (SCI) in the research process, the science of engagement and benefits of partnerships in research, and emerging resources available to help promote ethical and effective partnerships in SCI research. Recent findings Significant strides have been made in interacting with people living with SCI to help identify the problem(s) that are important to study (i.e. the first step in the research process). The SCI research field is lagging in partnering with people living with SCI throughout the rest of the research process despite a plethora of evidence-based principles and strategies for effective partnerships in the broader context of research. There are several emerging resources specific to SCI to help researchers and the community begin to build meaningful partnerships throughout the entire cycle of research. Summary The SCI research field already values partnerships with clinicians and promotes the concept of 'bench-to-bedside and back again'. Now is the time to take it a step further to 'bench-to-bedside-to-community and back again'.

IntroductionThis protocol is describing the first ever prospective, mock-efficacy, dose exploration trial design testing the feasibility of administering gabapentin in the acute setting as an intervention for neurorecovery. Gabapentin is an FDA-approved medication for treating seizures and postherpetic neuralgia and is used broadly off-label for neuropathic pain management for many conditions, including spinal cord injury. Emerging data suggests that when given early after spinal cord injury onset and in low-medium doses, gabapentin may have properties that promote recovery of neurological function. The objective of this trial is to assess the feasibility of conducting an efficacy trial in which gabapentin is started early after injury, is restricted in its dose, and is not used for pain management.Methods and analysisForty-two people aged 18 years or older with any level and any severity of spinal cord injury induced by a trauma will be enrolled, randomized, and have the first dose of study medication by 120 h post-injury onset. Participants will be randomly assigned to one of three groups: 600, 1,800 mg/day gabapentin, or placebo. Study medication will be given for a 90-day duration. Blinded assessments will be obtained at 7 days post-injury (baseline), 30 days post-injury (interim), after the 90-day treatment duration/approximately 3 months post-injury (end of treatment), and at 6 months post-injury (end of study). The key analysis parameters will evaluate feasibility of recruitment of target population, delivery of drug treatment protocol, maintenance of blinding, and retention of participants.DiscussionOutputs from this trial will inform research and clinical practice on the effects of manipulating gabapentin for non-pain management purposes in the acute setting and will guide the development of a properly powered efficacy trial of gabapentin as an intervention for neurorecovery in spinal cord injury.Ethics and disseminationThe study was approved by the MetroHealth Institutional Review Board (IRB21-00609) and registered at clinicaltrials.gov prior to enrolling any participants. Dissemination will include peer-reviewed publications, presentations at professional conferences and in the community, and through other healthcare and public venues.Clinical trial registrationwww.ClinicalTrials.gov, identifier: NCT05302999; protocol version 1.1 approved 05/23/2022.Trial fundingNational Institute on Disability, Independent Living and Rehabilitation Research.

Objective To address a gap between spinal cord injury (SCI) research and practice by rigorously and systematically co-developing integrated knowledge translation (IKT) guiding principles for conducting and disseminating SCI research in partnership with research users. Design The process was guided by the internationally accepted The Appraisal of Guidelines for REsearch & Evaluation (AGREE) II Instrument for evaluating the development of clinical practice guidelines. Setting North American SCI research system (ie, SCI researchers, research users, funders). Participants The multidisciplinary expert panel (n=17) and end users (n=35) included individuals from a North American partnership of SCI researchers, research users, and funders who have expertise in research partnerships. Interventions Not applicable. Main Outcome Measures Clarity, usefulness, and appropriateness of the principles. Results Data regarding 125 principles of partnered research were systematically collected from 4 sources (review of reviews, scoping review, interviews, Delphi consensus exercise). A multidisciplinary expert panel held a 2-day meeting to establish consensus, select guiding principles, and draft the guidance. The panel reached 100% consensus on the principles and guidance document. The final document includes a preamble, 8 guiding principles, and a glossary. Survey data showed that the principles and guidance document were perceived by potential end users as clear, useful, and appropriate. Conclusions The IKT Guiding Principles represent the first rigorously co-developed, consensus-based guidance to support meaningful SCI research partnerships. The principles are a foundational tool with the potential to improve the relevance and impact of SCI research, mitigate tokenism, and advance the science of IKT.

Objective: To provide an overview of clinical assessments and diagnostic tools, self-report measures (SRMs) and data sets used in neurogenic bladder and bowel (NBB) dysfunction and recommendations for their use with persons with spinal cord injury /disease (SCI/D). Methods: Experts in SCI/D conducted literature reviews, compiled a list of NBB related assessments and measures, reviewed their psychometric properties, discussed their use in SCI/D and issued recommendations for the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements (CDEs) guidelines. Results: Clinical assessments included 15 objective tests and diagnostic tools for neurogenic bladder and 12 for neurogenic bowel. Following a two-phase evaluation, eight SRMs were selected for final review with the Qualiveen and Short-Form (SF) Qualiveen and the Neurogenic Bowel Dysfunction Score (NBDS) being recommended as supplemental, highly-recommended due to their strong psychometrics and extensive use in SCI/D. Two datasets and other SRM measures were recommended as supplemental. Conclusion: There is no one single measure that can be used to assess NBB dysfunction across all clinical research studies. Clinical and diagnostic tools are here recommended based on specific medical needs of the person with SCI/D. Following the CDE for SCI studies guidelines, we recommend both the SF-Qualiveen for bladder and the NBDS for bowel as relatively short measures with strong psychometrics. Other measures are also recommended. A combination of assessment tools (objective and subjective) to be used jointly across the spectrum of care seems critical to best capture changes related to NBB and develop better treatments.

A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (n = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI.

Background: Although a number of experimental therapies for spinal cord injury (SCI) have recently emerged, few authors have examined the goals of individuals with SCI considering experimental therapies, and none have determined whether sociodemographic and injury-specific characteristics influence that engagement. Objectives: To determine (a) the goals of individuals with SCI who are considering experimental therapies; (b) whether sociodemographic factors, injury-specific characteristics, and concerns over adverse events influence those goals and/or participation in experimental therapies and clinical trials; and (c) whether people with SCI feel they have adequate information about experimental therapies and clinical trials. Methods: An online survey that yielded 364 responses. Results: Most respondents (83.7%) had sought information about experimental therapies, and just under half (47.8%) had received one. The most frequently cited functional goals were improvement in bowel and bladder function and elimination of dysreflexia (60.4%). Several goals were influenced by age and level and completeness of injury, and most respondents (93.4%) wanted more information about experimental therapies. Just over one-third (34.6%) of respondents had participated in a clinical trial, and nearly all (96.9%) wanted more information about them. Having received experimental therapies and participated in clinical trials was positively correlated with seeking SCI-specific care from an SCI specialist rather than from a primary care physician. Most (83.9%) respondents would avoid or be reluctant to engage with a medical center if they were made aware of harm done to trial participants. Conclusion: This work suggests that there are unmet information needs among people with SCI, specifically pertaining to experimental therapies and clinical trials. It also reveals that improved access to SCI specialists may enhance access to novel treatments and research efforts. Being made aware of harm to trial participants may influence the decision of individuals with SCI to seek care at or enroll in trials at these clinical sites.

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 (

The concept of a comprehensive and person-centred approach in healthcare is not new and it is the basic principle that is embedded in the International Classification of Functioning, Disability and Health (ICF) framework. However, the implementation of a comprehensive and person-centred approach has not been fully translated into research development in people living with spinal cord injuries (SCI). This approach in research is important as the perspectives of persons living with SCI should be equally valued drivers in any research intended to provide a direct or indirect outcome to people living with a SCI. This perspective paper will discuss some of the limiting factors and provide some examples of previous and current successful steps being taken towards the worldwide implementation of this approach. Finally, this paper will suggest some of the steps needed to implement this person-centred model in research in people with SCI.

STUDY OBJECTIVES: The purpose of this study was to determine sleep quality and presence of sleep disorders in participants with spinal cord injury (SCI). METHODS: A web-based survey, available online from February 2011 to July 2013, using validated sleep questionnaires, advertised via the internet and locally through SCI consumer organizations in the United States, Australia, New Zealand, and Canada, was designed to evaluate sleep in adults with self-reported SCI. Demographic characteristics and medical history were obtained from participant self-report. RESULTS: In our study population, 70% of the 304 participants were male with a mean age of 45 ± 13 years. The mean duration of injury was 16 ± 12 years. Cervical injuries were reported by 49% and thoracic injuries noted in 40% of participants. Increased sleep apnea risk was noted in 31% of participants, with 66% reporting snoring. Insomnia symptoms were reported by 54% of the respondents. Almost 40% of participants ranked their sleep quality as “fairly bad” to “very bad” in the previous month, 29% reported “often” or “almost always” waking up because of pain, and 22% had difficulty falling asleep because of leg cramps. In the past year, 27% of the respondents reported daily uncomfortable leg sensations and 28% found these leg symptoms to be “moderately to extremely distressing.” CONCLUSIONS: This study increases the awareness that insomnia, sleep apnea, and poor sleep quality are common in individuals with chronic SCI; often coexisting. There is a need for increased screening for sleep problems by healthcare providers taking care of individuals living with SCI. CITATION: Shafazand S, Anderson KD, Nash MS. Sleep complaints and sleep quality in spinal cord injury: a web-based survey. J Clin Sleep Med. 2019;15(5):719–724.

Human neural stem cell transplantation (HuCNS-SC®) is a promising central nervous system (CNS) tissue repair strategy in patients with stable neurological deficits from chronic spinal cord...

The present study was part of a larger mixed-methods study concerning facilitators and barriers to living with chronic pain after spinal cord injury. The agreement with themes obtained in qualitative interviews were quantified in a large online survey and overarching themes were defined by factor analysis. The present study aimed to define subgroups based on cluster analysis of the overarching themes’ factor scores and to compare the subgroups on pain-related variables. Three subgroups—high pain impact, moderate pain impact, and low pain impact—emerged. The high pain impact subgroup experienced severe pain with neuropathic pain characteristics; used pain medication, multiple coping strategies, and self-remedies; and considered information about pain and its management critical, but were not able to communicate well about their pain. The moderate pain impact subgroup carried on despite pain, considered pain information important, and used multiple approaches to manage their pain, but used less medication owing to concerns about side effects and addiction. The low pain impact subgroup considered information about pain, pain treatments, and communication regarding pain less important than the other subgroups did. This study suggests that treatment approaches need to be individually tailored not only to type of pain, but also to personal factors and preferences. Perspective People who experience significant pain impact after spinal cord injury use multiple approaches to manage their pain. Many have concerns about side effects and addiction, and consider information about pain and its management, including pharmacologic, nonpharmacologic, and self-remedies, a high priority. Therefore, patients’ personal preferences may provide additional tailoring options for patient-centered treatments.

Objective To investigate the frequency and consequences of wheelchair repairs, looking at the relationship to usage, components, out-of-pocket costs, number of days affecting the user, and factors associated with the need for repairs or consequences. Design Survey, cross-sectional. Setting Nine spinal cord injury (SCI) Model Systems centers. Participants Wheelchair users with SCI (N=533). Interventions Not applicable. Main Outcome Measures Cost and incidence of wheelchair repairs and consequences and wheelchair usage within the past 6 months. Results A total of 310 participants (56%) reported repairs, 127 (42%) of whom experienced at least 1 adverse consequence lasting a median of 5 days (interquartile range [IQR], 2-17.3 days). Repair rates were highest for the seating system, electronics, and tires. Participants were most often stranded at home or forced to use a backup chair. Median out-of-pocket costs were $150 (IQR, $50-$620). Active users, based on type of mobility and terrain, experienced more repairs and consequences than less active users. Repairs were more common among those who were Black (odds ratio [OR], 2.42) or power wheelchair (PWC) users (OR, 1.84), whereas consequences were more common among those who were Black (OR, 2.27), PWC (OR, 2.08) or power assist users (OR, 2.76), and those who had public insurance (OR, 1.70). Conclusions Wheelchair repairs continue to affect more than 50% of wheelchair users with significant financial and personal cost. High repair rates limited participation inside and outside of the home. Consequences lasted longer than 2 weeks for many and may be minimized by a working backup chair. Disparities exist based on participant and wheelchair factors; repairs and adverse consequences appear to hit those most vulnerable with the least financial resources. Costs may be a barrier to repair completion for some individuals. This ongoing problem of high repair rates and their associated effects requires action such as higher standards, access to quicker service, and better training of users on wheelchair maintenance and repair.

Study design An internet-based survey. Objectives To determine how individuals with spinal cord injury (SCI) access information about experimental therapies and clinical trials. To understand which factors influence receipt of and perceived trustworthiness of that information. Setting Two academic medical centers and an SCI organization. Methods Demographic information frequencies and percentages were calculated then analyzed using chi-square tests for independence. Fisher's exact test of independence was used to assess significance for contingency tables with categories containing expected counts below five. Results Three hundred sixty four persons with SCI participated in the survey. Most felt confident in their ability to evaluate SCI-specific information from a variety of sources, though SCI organizations and the medical literature were deemed the most reliable. Information from SCI specialists was deemed more credible than that from non-SCI specialists, but only 53.6% of participants had access to them. Nearly all (89.0%) respondents who had sought information about experimental therapies had found it online, while 51.4% of those who had participated in a clinical trial had been contacted by a research team. Only 8.4% of participants felt their medical teams offered them sufficient information about experimental therapies and clinical trials. Wealthier and more educated respondents were more knowledgeable about health-related resources on the internet. Nearly all participants (96.9%) expressed interest in learning more about trials related to SCI. Conclusions There is an information deficit among people with SCI pertaining to experimental therapies and clinical trials. It is exacerbated by lack of income, education, and access to SCI specialists.

Study design Expert workgroup consensus, focused literature review, and vetting via feedback from international presentations and spinal cord professional membership groups. Objectives Develop and refine a basic dataset to enable standardized documentation of physical therapy (PT) and occupational therapy (OT) interventions delivered in a controlled clinical trial intended to improve voluntary motor function. Setting International Expert Working Group. Methods An international working group with expertise in spinal cord injury, PT, OT, and measurement developed a draft of the International Spinal Cord Injury (ISCI) Physical Therapy-Occupational Therapy (PT-OT) Basic Data Set (BDS). Emphasis was placed on efficiency and practicality of use. The BDS was iteratively refined based on applicable literature, and feedback collected from presentations at the 2017 and 2019 International Spinal Cord Society meetings. Results The ISCI PT-OT BDS contains seven broad categories of interventions: bed/seated mobility, standing activities, walking/stairs, gross motor upper extremity, fine motor upper extremity, strength training, and endurance training. The first five categories are classified as activity-directed and the last two as impairment-directed interventions. Time spent on interventions per category is recorded in 15-min intervals. Conclusions The ISCI PT-OT BDS enables standardized documentation of PT-OT activity-directed or impairment-directed interventions. The ISCI PT-OT BDS is a documentation tool to facilitate evaluation of the influence of rehabilitation therapies on motor function in clinical trials of biologic or pharmacologic agents or rehabilitation technologies that are delivered in the clinical setting.

Objective Persistent neuropathic pain is a common and often severe consequence of spinal cord injury (SCI). There is a critical need to better understand how to overcome barriers and promote facilitators to optimal pain management. The present study was designed to identify, from the perspectives of persons living with SCI, their significant others, and SCI health care professionals, the barriers and facilitators to optimal pain management for intense neuropathic pain. Design Qualitative interviews. Setting University laboratory. Subjects People with SCI who had experienced intense neuropathic pain for a minimum of a year (N = 15), their significant others (N = 15), and SCI health care providers (N = 15). Methods Qualitative interviews were recorded, transcribed, and analyzed based on grounded theory using ATLAS.ti software. Results Inadequate access to care, information, or pain management expertise were frequently perceived barriers to optimal pain management across all three groups. Another major barrier was SCI stakeholders’ concerns regarding the risks of adverse effects and addiction to pain medication. Facilitators included having a better understanding of pain and available treatment options, effective patient–provider communication, resilience, and access to nonpharmacological treatment options. Conclusions Managing intense neuropathic pain poses significant challenges after SCI. SCI stakeholders felt that accessible treatment options were limited and primarily focused on pain medications with minimal benefit but with significant risks for addiction and adverse effects. Actionable facilitators to optimal pain management after SCI include education regarding neuropathic pain and treatment options for all stakeholders, better communication regarding neuropathic pain among stakeholders, and improved patient access to nonpharmacological treatment options.

Replication of previously developed prognostic model. In motor complete injuries at admission to rehabilitation, perform; (1) replication analyses of the relationships between ISNCSCI motor level and motor scores and SCIM and (2) novel analyses to determine if age and/or sex moderate relationship between neurological impairment and function. Admission to initial inpatient rehabilitation in the United States. Post-Hoc analyses of data collected as part of a separate study. Replication analyses: (1) Pearson’s correlation assessed relationship strength between neurologic impairment and function. (2) Multiple linear regression assessed if center or age influenced functional outcome. Novel analyses: (1) Moderated multiple regression assessed if age and/or sex moderated the lesion level-function relationship. Of the 406 datasets, 161 were motor complete injuries, and included in the analyses. Median time post injury at admission to rehabilitation was 19 days. Our replication analyses confirmed the neurologic and functional value of each spinal segment reported by the EM-SCI group (all p ≤ 0.018). We failed to confirm their reported age effect (p = 0.05) and non-effect of center (p = 0.037). Our novel analyses indicated that age coded as above/below 50 moderated the relationship between neurologic impairment and function (p = 0.038) in cervical injuries only, but that age coded as above/below 35 (all p ≥ 0.510) and sex (all p ≥ 0.465) did not. The neurological and functional value of each segment is consistent across very different healthcare settings in early and late sub-acute stages and minimally impacted by age and sex. Differences related to centers and age may confound efficacy trials. The Miami Project to Cure Paralysis; The Craig H. Neilsen Foundation (83492)

The rapid growth in data sharing presents new opportunities across the spectrum of biomedical research. Global efforts are underway to develop practical guidance for implementation of data sharing and open data resources. These include the recent recommendation of ‘FAIR Data Principles’, which assert that if data is to have broad scientific value, then digital representations of that data should be Findable, Accessible, Interoperable and Reusable (FAIR)(1). The spinal cord injury (SCI) research field has a long history of collaborative initiatives tat include sharing of preclinical research models and outcome measures. In addition, new tools and resources are being developed by the SCI research community to enhance opportunities for data sharing and access. With this in mind, the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) hosted a workshop on October 5–6, 2016 in Bethesda, MD, in collaboration with the Open Data Commons for Spinal Cord Injury (ODC-SCI) titled “Preclinical SCI Data: Creating a FAIR Share Community”. Workshop invitees were nominated by the workshop steering committee (co-chairs: ARF and VPL; members: AC, KDA, MSB, KF, LBJ, PGP, JMS), to bring together junior and senior level experts including preclinical and basic SCI researchers from academia and industry, data science and bioinformatics experts, investigators with expertise in other neurological disease fields, clinical researchers, members of the SCI community, and program staff representing federal and private funding agencies. The workshop and ODC-SCI efforts were sponsored by the International Spinal Research Trust (ISRT), the Rick Hansen Institute, Wings for Life, the Craig H. Neilsen Foundation and NINDS. The number of attendees was limited to ensure active participation and feedback in small groups. The goals were to examine the current landscape for data sharing in SCI research and provide a path to its future. Below are highlights from the workshop, including perspectives on the value of data sharing in SCI research, workshop participant perspectives and concerns, descriptions of existing resources and actionable directions for further engaging the SCI research community in a model that may be applicable to many other areas of neuroscience. This manuscript is intended to share these initial findings with the broader research community, and to provide talking points for continued feedback from the SCI field, as it continues to move forward in the age of data sharing.

Study design A cross-sectional stated-preference survey using direct-assessment questions. Objective To determine the relative value placed on different outcomes to be used in a pivotal trial for the upper extremity configuration of the Networked Neuroprosthesis (NNP) as well as the tolerance of the expected adverse event profile. Setting Academic medical center in the United States. Methods Distribution of an online survey to adults living with tetraplegia; extent of agreement with each question/statement was obtaining using a 1-7 Likert scale. Results There were 8 statements about potential benefits in arm/hand function; for all statements, more than 70% of participants rated the functions as "1-very important" to regain. There were variable degrees of concern related to risks that could occur during the 30-day post-surgical period and increasing degrees of concern related to risks that could occur in the first 5 years, potentially due to the device, based on the increasing degree of invasiveness of the intervention required to address the event. When analysing the results based on all degrees of interest, more than 64% of responders were interested in getting the NNP with a success rate threshold as low as 50% regardless of time post-injury. Chi-squared analyses revealed some associations between responses and sex, injury level, and injury duration; however, none of these were statistically significant upon post-hoc analysis. Conclusion Data here indicate that people with tetraplegia are highly interested in a range of arm/hand functions and are tolerant of expected risks that may be associated with implanted neuroprosthetics. Sponsorship The Institute for Functional Restoration funded this project through a sub-contract to K.D. Anderson from a larger Special Projects Award (grant number FP0020773) from the Craig H. Neilsen Foundation.

OBJECTIVEIn cell transplantation trials for spinal cord injury (SCI), quantifiable imaging criteria that serve as inclusion criteria are important in trial design. The authors’ institutional experience has demonstrated an overall high rate of screen failures. The authors examined the causes for trial exclusion in a phase I, open-lab clinical trial examining the role of autologous Schwann cell intramedullary transplantation. Specifically, they reviewed the imaging characteristics in people with chronic SCI that excluded applicants from the trial, as this was a common cause of screening failures in their study.METHODSThe authors reviewed MRI records from 152 people with chronic (> 1 year) SCI who volunteered for intralesional Schwann cell transplantation but were deemed ineligible by prospectively defined criteria. Rostral-caudal injury lesion length was measured along the long axis of the spinal cord in the sagittal plane on T2-weighted MRI. Other lesion characteristics, specifically those pertaining to lesion cavity structure resulting in trial exclusion, were recorded.RESULTSImaging records from 152 potential participants with chronic SCI were reviewed, 42 with thoracic-level SCI and 110 with cervical-level SCI. Twenty-three individuals (55%) with thoracic SCI and 70 (64%) with cervical SCI were not enrolled in the trial based on imaging characteristics. For potential participants with thoracic injuries who did not meet the screening criteria for enrollment, the average rostral-caudal sagittal lesion length was 50 mm (SD 41 mm). In applicants with cervical injuries who did not meet the screening criteria for enrollment, the average sagittal lesion length was 34 mm (SD 21 mm).CONCLUSIONSWhile screening people with SCI for participation in a cell transplantation clinical trial, lesion length or volume can exclude potential subjects who appear appropriate candidates based on neurological eligibility criteria. In planning future cell-based therapy trials, the limitations incurred by lesion size should be considered early due to the screening burden and impact on candidate selection.

The rationale for implantation of autologous human Schwann cells (SCs) in persons with subacute spinal cord injury (SCI) is based on evidence that transplanted SCs are neuroprotective, support local axonal plasticity, and are capable of myelinating axons. A Phase I clinical trial was conducted to evaluate the safety of autologous human SC transplantation into the injury epicenter of six subjects with subacute SCI. The trial was an open-label, unblinded, non-randomized, non-placebo controlled study with a dose escalation design and standard medical rehabilitation. Participants were paraplegics with neurologically complete, trauma-induced spinal lesions. Autologous SCs were cultured in vitro from a sural nerve harvested from each participant and injected into the epicenter of the spinal lesion. Outcome measures for safety were protocol compliance, feasibility, adverse events, stability of neurological level, absence of detectable mass lesion, and the emergence of clinically significant neuropathic pain or muscle spasticity no greater than expected for a natural course cohort. One year post-transplantation, there were no surgical, medical, or neurological complications to indicate that the timing or procedure for the cell transplantation was unsafe. There were no adverse events or serious adverse events related to the cell therapy. There was no evidence of additional spinal cord damage, mass lesion, or syrinx formation. We conclude that it is feasible to identify eligible candidates, appropriately obtain informed consent, perform a peripheral nerve harvest to obtain SCs within 5-30 days of injury, and perform an intra-spinal transplantation of highly purified autologous SCs within 4-7 weeks of injury.

Background Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). Objective To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. Methods Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI. Results Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant. Conclusion A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.

The Cethrin™ clinical trial was an open-label Phase I/IIa trial undertaken to assess the safety, tolerability, and neurological status of patients with acute spinal cord injury (SCI) who were treated with escalating doses of Cethrin, a therapeutic protein drug that inactivates Rho. Recruitment, motor scores, and data on adverse events of treated patients have been reported (Fehlings et al.).(24) While determining efficacy in a small open-label study is not possible, it is important to understand if the results warrant further clinical study, because clinical trial failures have wide ranging impacts. We have examined the clinical data to analyze time to recruitment and sensory outcomes, and compared the outcomes with available registry and placebo data. The average time to recruitment was 52 h, and there was a trend to improved sensory scores in treated patients with thoracic injury. An analysis of patients who recovered two motor levels or more suggests that there may be a larger responder population in the Cethrin-treated participants than in historical controls. We examined time to recruitment and found that the extent of motor and sensory recovery could not be explained by early surgery, and the Cethrin-treated patients showed favorable trends compared with the Surgical Timing in Acute SCI data. The trends reported here indicate that further study of Cethrin is warranted and provide useful guidance to establish effective clinical protocols.

Insufficient donor nerve graft material in peripheral nerve surgery remains an obstacle for successful long-distance regeneration. Schwann cells (SCs) can be isolated from adult mammalian peripheral nerve biopsies and can be grown in culture and retain their capacity to enhance peripheral nerve regeneration within tubular repair strategies in multiple animal models. Human Schwann cells (hSCs) can be isolated, expanded in number, and retain their ability to promote regeneration and myelinate axons, but have never been tested in a clinical case of peripheral nerve injury. A sural nerve biopsy and peripheral nerve tissue from the traumatized sciatic nerve stumps was obtained after Food and Drug Administration (FDA) and Institutional Review Board (IRB) approval as well as patient consent. The SCs were isolated after enzymatic digestion of the nerve and expanded with the use of heregulin β1 (0.1 μg/ml) and forskolin (15 mM). After two passages the Schwann cell isolates were combined with sural nerve grafts to repair a large sciatic nerve defect (7.5 cm) after a traumatic nerve injury. The sural nerve and the traumatized sciatic nerve ends both served as an excellent source of purified (90% and 97%, respectively) hSCs. Using ultrasound and magnetic resonance imaging (MRI) we were able to determine continuity of the nerve graft repair and the absence of tumor formation. The patient had evidence of proximal sensory recovery and definitive motor recovery distal to the repair in the distribution of the tibial and common peroneal nerve. The patient did experience an improvement in her pain scores over time. The goals of this approach were to determine the safety and clinical feasibility of implementing a new cellular repair strategy. In summary, this approach represents a novel strategy in the treatment of peripheral nerve injury and represents the first reported use of autologous cultured SCs after human peripheral nerve injury.

We recently demonstrated that the electrical perceptual threshold (EPT) examination reveals spared sensory function at lower spinal segments compared with the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) examination in humans with chronic incomplete cervical spinal cord injury (SCI). Here, we investigated whether discrepancies in sensory function detected by both sensory examinations change over time after SCI. Forty-five participants with acute (10 years) incomplete cervical SCI and 30 control subjects were tested on dermatomes C2–T4 bilaterally. EPT values were higher in subjects with acute (2.5 ± 0.8 mA), chronic (2.2 ± 0.7 mA), or extended-chronic (2.8 ± 1.1 mA) SCI compared with controls (1.0 ± 0.1 mA). The EPT examination detected sensory impairments in spinal segments above (2.3 ± 0.9) and below (4.2 ± 2.6) the level detected by the ISNCSCI sensory examination in participants with acute and chronic SCI, respectively. Notably, both examinations detected similar levels of spared sensory function in the extended-chronic phase of SCI (0.8 ± 0.5). A negative correlation was found between differences in EPT and ISNCSCI sensory levels and time post-injury. These observations indicate that discrepancies between EPT and ISNCSCI sensory scores are time-dependent, with the EPT revealing impaired sensory function above, below, or at the same spinal segment as the ISNCSCI examination. We propose that the EPT is a sensitive tool to assess changes in sensory function over time after incomplete cervical SCI.

Multi-center, prospective, cohort study. To assess the validity and reliability of the Spinal Cord Independence Measure (SCIM III) in measuring functional ability in persons with spinal cord injury (SCI). Inpatient rehabilitation hospitals in the United States (US). Functional ability was measured with the SCIM III during the first week of admittance into inpatient acute rehabilitation and within one week of discharge from the same rehabilitation program. Motor and sensory neurologic impairment was measured with the American Spinal Injury Association Impairment Scale. The Functional Independence Measure (FIM), the default functional measure currently used in most US hospitals, was used as a comparison standard for the SCIM III. Statistical analyses were used to test the validity and reliability of the SCIM III. Total agreement between raters was above 70% on most SCIM III tasks and all κ-coefficients were statistically significant (P

There is increasing motivation to develop clinically relevant experimental models for cervical SCI in rodents and techniques to assess deficits in forelimb function. Here we describe a bilateral cervical contusion model in rats. Female Sprague-Dawley rats received mild or moderate cervical contusion injuries (using the Infinite Horizons device) at C5, C6, or C7/8. Forelimb motor function was assessed using a Grip Strength Meter (GSM); sensory function was assessed by the von Frey hair test; the integrity of the corticospinal tract (CST) was assessed by biotinylated dextran amine (BDA) tract tracing. Mild contusions caused primarily dorsal column (DC) and gray matter (GM) damage while moderate contusions produced additional damage to lateral and ventral tissue. Forelimb and hindlimb function was severely impaired immediately post-injury, but all rats regained the ability to use their hindlimbs for locomotion. Gripping ability was abolished immediately after injury but recovered partially, depending upon the spinal level and severity of the injury. Rats exhibited a loss of sensation in both fore- and hindlimbs that partially recovered, and did not exhibit allodynia. Tract tracing revealed that the main contingent of CST axons in the DC was completely interrupted in all but one animal whereas the dorsolateral CST (dlCST) was partially spared, and dlCST axons gave rise to axons that arborized in the GM caudal to the injury. Our data demonstrate that rats can survive significant bilateral cervical contusion injuries at or below C5 and that forepaw gripping function recovers after mild injuries even when the main component of CST axons in the dorsal column is completely interrupted.

We describe here a novel forelimb locomotor assessment scale (FLAS) that assesses forelimb use during locomotion in rats injured at the cervical level. A quantitative scale was developed that measures movements of shoulder, elbow, and wrist joints, forepaw position and digit placement, forelimb-hindlimb coordination, compensatory behaviors adopted while walking, and balance. Female Sprague-Dawley rats received graded cervical contusions ranging from 200 to 230 ("mild," n=11) and 250-290 kdyn ("moderate," n=13) between C5 and C8. Rats were videotaped post-injury as they walked along an alley to determine deficits and recovery of forelimb function. Recovery of shoulder and elbow joint movement occurred rapidly (within 1-7 days post-injury), whereas recovery of wrist joint movement was slower and more variable. Most rats in all groups displayed persistent deficits in forepaw and digit movement, but developed compensatory behaviors to allow functional forward locomotion within 1-2 weeks post-injury. Recovery of forelimb function as measured by the FLAS reached a plateau by 3 weeks post-injury in all groups. Rats with mild contusions displayed greater locomotor recovery than rats with moderate contusions, but exhibited persistent deficits compared to sham controls. Reliability was tested by having seven raters (three internal, four external) from different laboratories, independently and blindly score videos of all rats. The multivariate correlation between all raters, all animals, and all time points ranged from r(2)=0.88-0.96 (p

Previous studies in mice have demonstrated that forepaw gripping ability, as measured by a grip strength meter (GSM), is dependent on the contralateral sensorimotor cortex, but this dependency changes after hemisection injury at cervical level 4 (C4). Initially, the mouse fails to grip with the forepaw ipsilateral to the hemisection but gripping recovers. Additionally, a mouse's gripping by the contralateral paw becomes independent of the sensorimotor cortex, indicating a reorganization of cortical control of gripping function (Blanco, J.E., Anderson, K.D., Steward, O. 2007. Recovery of forepaw gripping ability and reorganization of cortical motor control following cervical spinal cord injuries in mice. Exp. Neurol. 203, 333-348.). Here we explore whether a similar reorganization occurs after cervical hemisection injuries in rats. We show that as in mice, unilateral lesions of the sensorimotor cortex impair rats' griping by the contralateral paw. We also confirm from previous studies that cervical hemisections impair rats' griping by the ipsilateral paw. In contrast to mice, however there is minimal recovery of gripping after complete lateral hemisections and secondary lesions of the sensorimotor cortex continue to impair rats' gripping by the contralateral paw. Thus, forelimb gripping ability as measured by the GSM is dependent on the contralateral sensorimotor cortex in rats even after a cervical hemisection.

Secure, web-based survey.To determine how quadriplegics in the US view tendon transfer surgeries (TTS) and what activities of daily living (ADL) involving arm/hand function are important in improving quality of life (QoL).World wide web.Individualsor=18 years of age living with a cervical spinal cord injury (SCI). Participants obtained a pass code to enter a secure website and answered survey questions. A total of 137 participants completed the survey.Two-thirds of participants had injury levels between C4/5 and C5/6. Over 90% felt that improving their arm/hand function would improve their QoL. ADL that were ranked most important to regain were dressing, feeding, transferring in/out of bed, and handwriting. Less than half of the participants had never been told about TTS and only 9% had ever had TTS. Nearly 80% reported that they would be willing to spend 2-3 months being less independent, while recovering from surgery, to ultimately become more independent. Over 75% reported that the ideal time preferred to have TTS, if chosen, would be within 5 years post-injury.Regaining arm and hand function is of primary importance to individuals with cervical SCI, in particular, to increase independence in multiple ADL. There is a critical need in the US to improve awareness of TTS as a viable option for improving arm/hand function in some people. This information needs to be provided early after injury so that informed choices can be made within the first 5 years.

Background/Objective: The end goal of clinical care and clinical research involving spinal cord injury (SCI) is to improve the overall ability of persons living with SCI to function on a daily basi...

These are exciting times for the translation of promising interventions for spinal cord injury (SCI) into testing with clinical trials. These interventions include acute surgical decompression, neuroprotection, neural repair, cell replacement, activity-based rehabilitation, and medical devices, including devices requiring surgical implantation. By nature, clinical trials can have strict inclusion and exclusion criteria, which narrow down the pool of potential participants. Meeting enrollment numbers for properly powered trials is a daunting task. Therefore, it is important that trials are designed in a manner that facilitates participation. The purpose of this research study was to learn more about the factors that encourage or interfere with the decision to participate in clinical trials from the perspective of people living with SCI. A multi-national survey was conducted, primarily online, in which 802 participants with SCI ranked 32 factors as facilitators or barriers, using a Likert-type scale. There were 13 universal facilitators, five universal barriers, and three universally neutral factors. The number one facilitator was possible improvement in functionality and the number one barrier was possible decline in functionality--as may be expected. However, many unexpected facilitators and barriers were identified. There also were certain factors that were strong barriers or facilitators to certain sub-groups of people living with SCI. All of these factors should be taken into careful consideration when designing clinical trials so as to promote enrollment and enable adherence to different protocols.

Objective. One of the main goals of brain–machine interface (BMI) research is to restore function to people with paralysis. Currently, multiple BMI design features are being investigated, based on various input modalities (externally applied and surgically implantable sensors) and output modalities (e.g. control of computer systems, prosthetic arms, and functional electrical stimulation systems). While these technologies may eventually provide some level of benefit, they each carry associated burdens for end-users. We sought to assess the attitudes of people with paralysis toward using various technologies to achieve particular benefits, given the burdens currently associated with the use of each system. Approach. We designed and distributed a technology survey to determine the level of benefit necessary for people with tetraplegia due to spinal cord injury to consider using different technologies, given the burdens currently associated with them. The survey queried user preferences for 8 BMI technologies including electroencephalography, electrocorticography, and intracortical microelectrode arrays, as well as a commercially available eye tracking system for comparison. Participants used a 5-point scale to rate their likelihood to adopt these technologies for 13 potential control capabilities. Main Results. Survey respondents were most likely to adopt BMI technology to restore some of their natural upper extremity function, including restoration of hand grasp and/or some degree of natural arm movement. High speed typing and control of a fast robot arm were also of interest to this population. Surgically implanted wireless technologies were twice as ‘likely’ to be adopted as their wired equivalents. Significance. Assessing end-user preferences is an essential prerequisite to the design and implementation of any assistive technology. The results of this survey suggest that people with tetraplegia would adopt an unobtrusive, autonomous BMI system for both restoration of upper extremity function and control of external devices such as communication interfaces.

To develop a comprehensive set of common data elements (CDEs), data definitions, case report forms and guidelines for use in spinal cord injury (SCI) clinical research, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health.International Working Groups.Nine working groups composed of international experts reviewed existing CDEs and instruments, created new elements when needed and provided recommendations for SCI clinical research. The project was carried out in collaboration with and cross-referenced to development of the International Spinal Cord Society (ISCoS) International SCI Data Sets. The recommendations were compiled, subjected to internal review and posted online for external public comment. The final version was reviewed by all working groups and the NINDS CDE team before release.The NINDS SCI CDEs and supporting documents are publically available on the NINDS CDE website and the ISCoS website. The CDEs span the continuum of SCI care and the full range of domains of the International Classification of Functioning, Disability and Health.Widespread use of CDEs can facilitate SCI clinical research and trial design, data sharing and retrospective analyses. Continued international collaboration will enable consistent data collection and reporting, and will help ensure that the data elements are updated, reviewed and broadcast as additional evidence is obtained.

Secure, web-based survey.Elicit specific information about sexual function from women with spinal cord injuries (SCI).World-wide web.Individuals 18 years or older living with SCI obtained a pass code to enter a secure website and then answered survey questions.Bladder and/or bowel incontinence during sexual activity and/or sexual intercourse were significant concerns and prevented some women from seeking sexual activity. Autonomic dysreflexia (AD) during sexual activity was interpreted negatively by many and was found to interfere with sexual activity. Most subjects reported difficulty becoming psychologically aroused as well as physically aroused, which were both correlated with feeling that their SCI had altered their sexual sense of self. An inverse relationship existed between developing new areas of arousal above the level of lesion and not having sensation or movement below the lesion. The most commonly reported sexual stimulation leading to the best arousal involved stimulation of the head/neck and torso areas. The majority of subjects reported having experienced intercourse postinjury. Most participants reported difficulty with positioning during foreplay and intercourse, vaginal lubrication, and spasticity during intercourse. Almost half reported experiencing orgasm postinjury and this was positively associated with the presence of genital sensation.SCI significantly impairs psychological and physical aspects of female sexual arousal. In addition, bladder and bowel incontinence as well as AD negatively impact sexual activity and intercourse.

The neuronal-specific RNA-binding protein, HuD, binds to a U-rich regulatory element of the 3' untranslated region (3' UTR) of the GAP-43 mRNA and delays the onset of its degradation. We have recently shown that overexpression of HuD in embryonic rat cortical cells accelerated the time course of normal neurite outgrowth and resulted in a twofold increase in GAP-43 mRNA levels. Given this evidence, we sought to investigate the involvement of HuD during nerve regeneration. It is known that HuD protein and GAP-43 mRNA are expressed in the dorsal root ganglia (DRG) of adult rat and that GAP-43 is upregulated in DRG neurons during regeneration. In this study, we examined the expression patterns and levels of HuD and GAP-43 mRNA in DRG neurons following sciatic nerve injury using a combination of in situ hybridization, immunocytochemistry, and quantitative RT-PCR. GAP-43 and HuD expression increased in the ipsilateral DRG during the first 3 weeks of regeneration, with peak values seen at 7 days postcrush. At this time point, the levels of HuD and GAP-43 mRNAs in the ipsilateral DRG increased by twofold and sixfold, respectively, relative to the contralateral DRG. Not only were the temporal patterns of expression of HuD protein and GAP-43 mRNA similar, but also they were found to colocalize in the cytoplasm of DRG neurons. Moreover, both molecules were distributed in cytoplasmic granules containing ribosomal RNA. In conclusion, our results suggest that HuD is involved in the upregulation of GAP-43 expression observed at early stages of peripheral nerve regeneration.

OBJECTIVE Long-segment injuries to large peripheral nerves present a challenge to surgeons because insufficient donor tissue limits repair. Multiple supplemental approaches have been investigated, including the use of Schwann cells (SCs). The authors present the first 2 cases using autologous SCs to supplement a peripheral nerve graft repair in humans with long-term follow-up data. METHODS Two patients were enrolled in an FDA-approved trial to assess the safety of using expanded populations of autologous SCs to supplement the repair of long-segment injuries to the sciatic nerve. The mechanism of injury included a boat propeller and a gunshot wound. The SCs were obtained from both the sural nerve and damaged sciatic nerve stump. The SCs were expanded and purified in culture by using heregulin β1 and forskolin. Repair was performed with sural nerve grafts, SCs in suspension, and a Duragen graft to house the construct. Follow-up was 36 and 12 months for the patients in Cases 1 and 2, respectively. RESULTS The patient in Case 1 had a boat propeller injury with complete transection of both sciatic divisions at midthigh. The graft length was approximately 7.5 cm. In the postoperative period the patient regained motor function (Medical Research Council [MRC] Grade 5/5) in the tibial distribution, with partial function in peroneal distribution (MRC Grade 2/5 on dorsiflexion). Partial return of sensory function was also achieved, and neuropathic pain was completely resolved. The patient in Case 2 sustained a gunshot wound to the leg, with partial disruption of the tibial division of the sciatic nerve at the midthigh. The graft length was 5 cm. Postoperatively the patient regained complete motor function of the tibial nerve, with partial return of sensation. Long-term follow-up with both MRI and ultrasound demonstrated nerve graft continuity and the absence of tumor formation at the repair site. CONCLUSIONS Presented here are the first 2 cases in which autologous SCs were used to supplement human peripheral nerve repair in long-segment injury. Both patients had significant improvement in both motor and sensory function with correlative imaging. This study demonstrates preliminary safety and efficacy of SC transplantation for peripheral nerve repair.

Efforts to understand spinal cord injury (SCI) and other complex neurotrauma disorders at the pre-clinical level have shown progress in recent years. However, successful translation of basic research into clinical practice has been slow, partly because of the large, heterogeneous data sets involved. In this sense, translational neurological research represents a "big data" problem. In an effort to expedite translation of pre-clinical knowledge into standards of patient care for SCI, we describe the development of a novel database for translational neurotrauma research known as Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI). We present demographics, descriptive statistics, and translational syndromic outcomes derived from our ongoing efforts to build a multi-center, multi-species pre-clinical database for SCI models. We leveraged archived surgical records, postoperative care logs, behavioral outcome measures, and histopathology from approximately 3000 mice, rats, and monkeys from pre-clinical SCI studies published between 1993 and 2013. The majority of animals in the database have measures collected for health monitoring, such as weight loss/gain, heart rate, blood pressure, postoperative monitoring of bladder function and drug/fluid administration, behavioral outcome measures of locomotion, and tissue sparing postmortem. Attempts to align these variables with currently accepted common data elements highlighted the need for more translational outcomes to be identified as clinical endpoints for therapeutic testing. Last, we use syndromic analysis to identify conserved biological mechanisms of recovery after cervical SCI between rats and monkeys that will allow for more-efficient testing of therapeutics that will need to be translated toward future clinical trials.

Background. A quadratic formula of the Spinal Cord Injury Ability Realization Measurement Index (SCI-ARMI) has previously been published. This formula was based on a model of Spinal Cord Independence Measure (SCIM95), the 95th percentile of the SCIM III values, which correspond with the American Spinal Injury Association Motor Scores (AMS) of SCI patients. Objective. To further develop the original formula. Setting. Spinal cord injury centers from 6 countries and the Statistical Laboratory, Tel-Aviv University, Israel. Methods. SCIM95 of 661 SCI patients was modeled, using a quantile regression with or without adjustment for age and gender, to calculate SCI-ARMI values. SCI-ARMI gain during rehabilitation and its correlations were examined. Results. A new quadratic SCIM95 model was created. This resembled the previously published model, which yielded similar SCIM95 values in all the countries, after adjustment for age and gender. Without this adjustment, however, only 86% of the non-Israeli SCIM III observations were lower than those SCIM95 values ( P < .0001). Adding the variables age and gender to the new model affected the SCIM95 value significantly ( P < .04). Adding country information did not add a significant effect ( P > .1). SCI-ARMI gain was positive (38.8 ± 22 points, P < .0001) and correlated weakly with admission age and AMS. Conclusions. The original quadratic SCI-ARMI formula is valid for an international population after adjustment for age and gender. The new formula considers more factors that affect functional ability following SCI.

The RNA-binding protein HuD binds to a regulatory element in the 3′ untranslated region (3′ UTR) of the GAP-43 mRNA. To investigate the functional significance of this interaction, we generated PC12 cell lines in which HuD levels were controlled by transfection with either antisense (pDuH) or sense (pcHuD) constructs. pDuH-transfected cells contained reduced amounts of GAP-43 protein and mRNA, and these levels remained low even after nerve growth factor (NGF) stimulation, a treatment that is normally associated with protein kinase C (PKC)-dependent stabilization of the GAP-43 mRNA and neuronal differentiation. Analysis of GAP-43 mRNA stability demonstrated that the mRNA had a shorter half-life in these cells. In agreement with their deficient GAP-43 expression, pDuH cells failed to grow neurites in the presence of NGF or phorbol esters. These cells, however, exhibited normal neurite outgrowth when exposed to dibutyryl-cAMP, an agent that induces outgrowth independently from GAP-43. We observed opposite effects in pcHuD-transfected cells. The GAP-43 mRNA was stabilized in these cells, leading to an increase in the levels of the GAP-43 mRNA and protein. pcHuD cells were also found to grow short spontaneous neurites, a process that required the presence of GAP-43. In conclusion, our results suggest that HuD plays a critical role in PKC-mediated neurite outgrowth in PC12 cells and that this protein does so primarily by promoting the stabilization of the GAP-43 mRNA.

Effective treatment after cervical spinal cord injury (SCI) is imperative as so many activities of daily living (ADLs) are dependent on functional recovery of arm and hand actions. We focus on defining and comparing neurological and functional endpoints that might be used during acute or subacute Phase 2 clinical trials involving subjects with cervical sensorimotor complete SCI (ASIA Impairment Scale [AIS-A]). For the purposes of this review, the trial would examine the effects of a pharmaceutical small molecule, drug, biologic, or cell transplant on spinal tissue. Thus, neurological improvement is the intended consequence and is most directly measured by assessing neurological impairment (eg, motor aspects of the International Standards Neurological Classification of Spinal Cord Injury [ISNCSCI]). However, changes in neurological function, even if statistically significant, may not be associated with a clear functional impact (ie, a meaningful improvement in individual activity, such as independent self-care ADLs). The challenge is to measure improvement as precisely as possible (change in impairment), but to define a clinically meaningful response in the context of functional improvement (impact on activity limitations). The principal comparisons focused on elements of the ISNCSCI assessment, including upper extremity motor score and motor level. Personal activity capabilities were also examined at various time points. The data suggest that an improvement of 2 or more motor levels after cervical sensorimotor complete SCI may be a clinically meaningful endpoint threshold that could be used for acute and subacute Phase 2 trials with subjects having sensorimotor complete cervical SCI.

Objective: To summarize research to understand the priorities of consumers with spinal cord injury (SCI) as related to neuroprosthesis. Materials and Methods: This review is generated from results presented during a session at the 2008 Neural Interfaces Conference held in Cleveland, OH including presentations of research, observation of a panel discussion, and a case study. Results: Understanding priorities of consumers living with SCI may help guide development of technology to potentially increase quality of life, confidence, and independence. Those living with quadriplegia desire arm and hand function while persons with paraplegia wish to regain sexual function. Shared priorities in the SCI population are the restoration of bladder and bowel function and the importance of exercise for functional recovery. Conclusion: Understanding the consumer is the cornerstone to successful delivery of a neuroprosthesis. Translational research by multidisciplinary teams is needed to understand these issues and move technology for people living with SCI from the bench to the bedside.