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Background Spinal cord stimulation (SCS) clinical trials are evaluating its efficacy and safety for motor, sensory, and autonomic recovery following spinal cord injury (SCI). The perspectives of people living with SCI are not well known and can inform the planning, delivery, and translation of SCS. Objectives To obtain input from people living with SCI on the top priorities for recovery, expected meaningful benefits, risk tolerance, clinical trial design, and overall interest in SCS. Methods Data were collected anonymously from an online survey between February and May 2020. Results A total of 223 respondents living with SCI completed the survey. The majority of respondents identified their gender as male (64%), were 10+ years post SCI (63%), and had a mean age of 50.8 years. Most individuals had a traumatic SCI (81%), and 45% classified themselves as having tetraplegia. Priorities for improved outcome for those with complete or incomplete tetraplegia included fine motor skills and upper body function, whereas priorities for complete or incomplete paraplegia included standing and walking, and bowel function. The meaningful benefits that are important to achieve are bowel and bladder care, less reliance on caregivers, and maintaining physical health. Perceived potential risks include further loss of function, neuropathic pain, and complications. Barriers to participation in clinical trials include inability to relocate, out-of-pocket expenses, and awareness of therapy. Respondents were more interested in transcutaneous SCS than epidural SCS (80% and 61%, respectively). Conclusion SCS clinical trial design, participant recruitment, and translation of the technology can be improved by better reflecting the priorities and preferences of those living with SCI identified from this study.

Background Context Current prognostic tools such as the Injury Severity Score (ISS) that predict mortality following trauma do not adequately consider the unique characteristics of traumatic spinal cord injury (tSCI). Purpose Our aim was to develop and validate a prognostic tool that can predict mortality following tSCI. Study Design Retrospective review of a prospective cohort study. Patient Sample Data was collected from 1245 persons with acute tSCI who were enrolled in the Rick Hansen Spinal Cord Injury Registry between 2004-2016. Outcome Measures In-hospital and one-year mortality following tSCI. Methods Machine learning techniques were used on patient-level data (n=849) to develop the Spinal Cord Injury Risk Score (SCIRS) that can predict mortality based on age, neurological level and completeness of injury, AOSpine classification of spinal column injury morphology, and Abbreviated Injury Scale scores. Validation of the SCIRS was performed by testing its accuracy in an independent validation cohort (n=396) and comparing its performance to the ISS, a measure which is used to predict mortality following general trauma. Results For one-year mortality prediction, the values for the Area Under the Receiver Operating Characteristic Curve (AUC) for the development cohort were 0.84 (standard deviation=0.029) for the SCIRS and 0.55 (0.041) for the ISS. For the validation cohort, AUC values were 0.86 (0.051) for the SCIRS and 0.71 (0.074) for the ISS. For in-hospital mortality, AUC values for the development cohort were 0.87 (0.028) and 0.60 (0.050) for the SCIRS and ISS, respectively. For the validation cohort, AUC values were 0.85 (0.054) for the SCIRS and 0.70 (0.079) for the ISS. Conclusions The SCIRS can predict in-hospital and one-year mortality following tSCI more accurately than the ISS. The SCIRS can be used in research to reduce bias in estimating parameters and can help adjust for coefficients during model development. Further validation using larger sample sizes and independent datasets is needed to further assess its reliability and to evaluate using it as an assessment tool to guide clinical decision-making and discussions with patients and families.

Background: To optimize traumatic spinal cord injury (tSCI) care, administrative and clinical linked data are required to describe the patient’s journey. Objectives: To describe the methods and progress to deterministically link SCI data from multiple databases across the SCI continuum in British Columbia (BC) and Ontario (ON) to answer epidemiological and health service research questions. Methods: Patients with tSCI will be identified from the administrative Hospital Discharge Abstract Database using International Classification of Diseases (ICD) codes from Population Data BC and ICES data repositories in BC and ON, respectively. Admissions for tSCI will range between 1995–2017 for BC and 2009-2017 for ON. Linkage will occur with multiple administrative data holdings from Population Data BC and ICES to create the “Admin SCI Cohorts.” Clinical data from the Rick Hansen SCI Registry (and VerteBase in BC) will be transferred to Population Data BC and ICES. Linkage of the clinical data with the incident cases and administrative data at Population Data BC and ICES will create subsets of patients referred to as the “Clinical SCI Cohorts” for BC and ON. Deidentified patient-level linked data sets will be uploaded to a secure research environment for analysis. Data validation will include several steps, and data analysis plans will be created for each research question. Discussion: The creation of provincially linked tSCI data sets is unique; both clinical and administrative data are included to inform the optimization of care across the SCI continuum. Methods and lessons learned will inform future data-linking projects and care initiatives.

To describe the status of spinal cord stimulation (SCS) research for the improvement of motor, sensory, and autonomic function for individuals living with a spinal cord injury (SCI).This scoping review identified original research published before March 31, 2021, via literature searches using MEDLINE, Embase, PubMed, Science Direct, Cumulative Index to Nursing and Allied Health, Sport Discus, and Web of Science, as well as a targeted search for well-known principal investigators. Search terms included permutations of "spinal cord stimulation," "epidural spinal cord stimulation," "transcutaneous spinal cord stimulation," "magnetic spinal cord stimulation," and "neuromodulation."Studies were included if they (1) were in English, (2) presented original research on humans living with a SCI, and (3) investigated at least 1 of the 3 forms of SCS.Extracted data included authors, publication year, participant characteristics, purpose, study design, stimulation (device, location, parameters), primary outcomes, and adverse events.As a scoping review the extracted data were tabulated and presented descriptively. Themes and gaps in the literature were identified and reported. Of the 5754 articles screened, 103 articles were included (55 epidural, 36 transcutaneous, 12 magnetic). The primary research design was a case study or series with only a single randomized controlled trial. Motor recovery was the most common primary outcome for epidural and transcutaneous SCS studies, whereas bowel and bladder outcomes were most common for magnetic SCS studies. Seventy percent of the studies included 10 or fewer participants, and 18 articles documented at least 1 adverse event. Incomplete stimulation parameter descriptions were noted across many studies. No articles mentioned direct engagement of consumers or advocacy groups.This review identified a need for more robust study designs, larger sample sizes, comparative studies, improved reporting of stimulation parameters, adverse event data, and alignment of outcomes with the priorities of the community with SCI.

Cohort study. It is widely accepted that the prediction of long-term neurologic outcome after traumatic spinal cord injury (SCI) can be done more accurately with neurological examinations conducted days to weeks post injury. However, modern clinical trials of neuroprotective interventions often require patients be examined and enrolled within hours. Our objective was to determine whether variability in timing of neurological examinations within 48 h after SCI is associated with differences in observations of follow-up neurologic recovery. Level I trauma hospital. An observational analysis testing for differences in AIS conversion rates and changes in total motor scores by neurological examination timing, controlling for potential confounders with multivariate stepwise regression. We included 85 patients, whose mean times from injury to baseline and follow-up examinations were 11.8 h (SD 9.8) and 208.2 days (SD 75.2), respectively. AIS conversion by 1+ grade was significantly more likely in patients examined at ≤4 h in comparison with later examination (78% versus 47%, RR = 1.66, p = 0.04), even after controlling for timing of surgery, age, and sex (OR 5.0, 95% CI 1.1–10, p = 0.04). We failed to identify any statistically significant associations for total motor score recovery in unadjusted or adjusted analyses. AIS grade conversion was significantly more likely in those examined ≤4 h of injury; the effect of timing on motor scores remains uncertain. Variability in neurological examination timing within hours after acute traumatic SCI may influence observations of long-term neurological recovery, which could introduce bias or lead to errors in interpretation of studies of therapeutic interventions.

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

International collaboration in spinal cord injury (SCI) research is necessary to overcome the challenges often encountered by clinicians and researchers, including participant recruitment, high cost, and the need for specialized expertise. However, international collaboration poses its own obstacles. The objective of this study was to conduct an international online survey to assess barriers and facilitators to international SCI clinical research, potential initiatives to facilitate future collaborations, and the use of SCI-specific data sets and standards. Results were analyzed using descriptive statistics. Of 364 total respondents, 213 completed the survey, with the majority of these participants based in North America (38%), Asia (22%), Europe (18%), and Oceania (16%). Over half had more than 10 years of experience in SCI research or clinical practice (57%) and 60% had previous experience with international collaborations. Funding was identified as a top barrier (82%), a facilitator (93%), and a proposed future initiative (97%). Communication and technology were also identified as strong facilitators and proposed future initiatives. The International Standards for Neurological Classification of SCI were used by 69% of participants, the International Standards to document remaining Autonomic Function after SCI by 13% of participants, and the International SCI Data Sets by 45% of participants. As the need for international collaborations in SCI research increases, it is important to identify how clinicians and researchers can be supported by SCI consumer and professional organizations, funders, and networks. Furthermore, unique solutions to overcome modifiable barriers and creation of new facilitators are also needed.

Burst-firing in thalamic neurons is known to play a key role in mediating thalamocortical (TC) oscillations that are associated with non-REM sleep and some types of epileptic seizure. Within the TC system the primary output of GABAergic neurons in the reticular thalamic nucleus (RTN) is thought to induce the de-inactivation of T-type calcium channels in thalamic relay (TR) neurons, promoting burst-firing drive to the cortex and the propagation of TC network activity. However, RTN neurons also project back onto other neurons within the RTN. The role of this putative negative feedback upon the RTN itself is less well understood, although is hypothesized to induce de-synchronization of RTN neuron firing leading to the suppression of TC oscillations. Here we tested two hypotheses concerning possible mechanisms underlying TC oscillation modulation. Firstly, we assessed the burst-firing behavior of RTN neurons in response to GABAB receptor activation using acute brain slices. The selective GABAB receptor agonist baclofen was found to induce suppression of burst-firing concurrent with effects on membrane input resistance. Secondly, RTN neurons express CaV3.2 and CaV3.3 T-type calcium channel isoforms known to contribute toward TC burst-firing and we examined the modulation of these channels by GABAB receptor activation. Utilizing exogenously expressed T-type channels we assessed whether GABAB receptor activation could directly alter T-type calcium channel properties. Overall, GABAB receptor activation had only modest effects on CaV3.2 and CaV3.3 isoforms. The only effect that could be predicted to suppress burst-firing was a hyperpolarized shift in the voltage-dependence of inactivation, potentially causing lower channel availability at membrane potentials critical for burst-firing. Conversely, other effects observed such as a hyperpolarized shift in the voltage-dependence of activation of both CaV3.2 and CaV3.3 as well as increased time constant of activation of the CaV3.3 isoform would be expected to enhance burst-firing. Together, we hypothesize that GABAB receptor activation mediates multiple downstream effectors that combined act to suppress burst-firing within the RTN. It appears unlikely that direct GABAB receptor-mediated modulation of T-type calcium channels is the major mechanistic contributor to this suppression.

Heantos-4 is a refined combination of plant extracts currently approved to treat opiate addiction in Vietnam. In addition to its beneficial effects on withdrawal and prevention of relapse, reports of sedation during clinical treatment suggest that arousal networks in the brain may be recruited during Heantos administration. T-type calcium channels are implicated in the generation of sleep rhythms and in this study we examined whether a Heantos-4 extraction modulates T-type calcium channel currents generated by the Cav3.1, Cav3.2 and Ca3.3 subtypes. Utilizing whole-cell voltage clamp on exogenously expressed T-type calcium channels we find that Heantos inhibits Cav3.1 and Cav3.3 currents, while selectively potentiating Cav3.2 currents. We further examined the effects of Heantos-4 extract on low-threshold burst-firing in thalamic neurons which contribute to sleep oscillations. Using whole-cell current clamp in acute thalamic brain slices Heantos-4 suppressed rebound burst-firing in ventrobasal thalamocortical neurons, which express primarily Cav3.1 channels. Conversely, Heantos-4 had no significant effect on the burst-firing properties of thalamic reticular neurons, which express a mixed population of Cav3.2 and Cav3.3 channels. Examining Heantos-4 effects following oral administration in a model of absence epilepsy revealed the potential to exacerbate seizure activity. Together, the findings indicate that Heantos-4 has selective effects both on specific T-type calcium channel isoforms and distinct populations of thalamic neurons providing a putative mechanism underlying its effects on sedation and on the thalamocortical network.

We used MCF-7 human breast cancer cells that endogenously express Cav3.1 and Cav3.2 T-type Ca2+ channels toward a mechanistic study on the effect of EGCG on [Ca2+](i). Confocal Ca2+ imaging showed that EGCG induces a [Ca2+](i) spike which is due to extracellular Ca2+ entry and is sensitive to catalase and to low-specificity (mibefradil) and high-specificity (Z944) T-type Ca(2+)channel blockers. siRNA knockdown of T-type Ca2+ channels indicated the involvement of Cav3.2 but not Cav3.1. Application of EGCG to HEK cells expressing either Cav3.2 or Cav3.1 induced enhancement of Cav3.2 and inhibition of Cav3.1 channel activity. Measurements of K+ currents in MCF-7 cells showed a reversible, catalase-sensitive inhibitory effect of EGCG, while siRNA for the Kv1.1 K+ channel induced a reduction of the EGCG [Ca2+](i) spike. siRNA for Cav3.2 reduced EGCG cytotoxicity to MCF-7 cells, as measured by calcein viability assay. Together, data suggest that EGCG promotes the activation of Cav3.2 channels through K+ current inhibition leading to membrane depolarization, and in addition increases Cav3.2 currents. Cav3.2 channels are in part responsible for EGCG inhibition of MCF-7 viability, suggesting that deregulation of [Ca2+](i) by EGCG may be relevant in breast cancer treatment. (C) 2014 Elsevier Ltd. All rights reserved.