Subacute Spinal Cord Injury Research Articles

Feasibility and safety of two weeks of blood flow restriction exercise in individuals with spinal cord injury

Context Reduced muscle strength and function are common after spinal cord injury (SCI). While low-load blood flow restriction exercise (BFRE) enhances muscle strength in healthy and clinical populations, its safety and feasibility in individuals with SCI remain underexplored. Objectives To investigate the feasibility and safety of low-load BFRE in individuals with incomplete SCI. Study Design Case series. Setting SCI rehabilitation center. Participants Six participants with motor incomplete SCI were enrolled in the study. Intervention A two-week BFRE intervention for the lower limbs was conducted twice weekly at 40% total arterial occlusion pressure, using 30-40% of 1-repetition maximum loads. Outcome Measures Feasibility measures, specifically recruitment and eligibility rates and intervention acceptability, were collected. Blood pressure (BP) responses and specific coagulation markers for deep vein thrombosis (DVT) were assessed as safety measures. Results Recruitment and eligibility rates were 2.8% and 6.6% for individuals admitted for first-time rehabilitation (subacute SCI) and 8.3% and 13.9% for 4-week readmission rehabilitation stays (chronic SCI), respectively. Intervention acceptability was high, characterized by 95.8% training adherence and low-to-moderate self-reported pain levels. BP responses and changes in C-reactive protein, Fibrinogen, and D-dimer during the intervention remained within clinically acceptable levels. Conclusion BFRE was feasible in an SCI rehabilitation setting despite a low recruitment rate. BFRE imposed no heightened risk of DVT or severe BP fluctuations in the present case series. Additionally, no severe adverse events occurred, and only mild complaints were reported. More extensive safety considerations warrant larger-scale exploration. Trial registration ClinicalTrials.gov identifier: NCT03690700.

No impact of anti-inflammatory medication on inflammation-driven recovery following cervical spinal cord injury in rats

Following spinal cord injury (SCI), inflammation is associated with the exacerbation of damage to spinal tissue. Consequently, managing inflammation during the acute and subacute phases is a common target in SCI treatment. However, inflammation may also induce potential benefits, including the stimulation of neuroplasticity and repair. This positive role of inflammation in spinal cord healing and functional recovery is not fully understood. To address this knowledge gap, we examined the effects of two common anti-inflammatory medications, Diphenhydramine and Methylprednisolone, on the efficacy of rehabilitative motor training on recovery from subacute cervical SCI in adult rats. Training depends critically on neuroplasticity thus if inflammation is a key regulator, we propose that anti-inflammatory drugs will reduce subsequent recovery. Both drugs were administered orally over one month, alongside task-specific reaching and grasping training.After treatment, no substantial changes in motor recovery or lesion size between the treated and control groups were observed. Treated animals also did not show any discernible changes in sensory function or anxiety-like behavior. Taken together, our data indicate that the prolonged use of these anti-inflammatory agents at commonly used doses did not profoundly impact recovery following an SCI. Therefore, considering earlier reports of the benefits of pro-inflammatory stimuli on plasticity, further studies in this area are imperative to elucidate the true impact of treating inflammation and its implications for recovery after spinal cord injuries.

Reliability of the Mini-BESTest and Brief-BESTest for assessing patients with incomplete spinal cord injury.

Single institution observational study. To investigate the ceiling and floor effects of the Berg Balance Scale (BBS), Mini-Balance Evaluation Systems Test (BESTest), and Brief-BESTest, as well as to determine the intra- and inter-rater reliabilities and minimal detectable change (MDC) of the Mini-BESTest and Brief-BESTest in patients with acute and subacute incomplete cervical spinal cord injury (SCI) classified as AIS D. Advanced critical care center of our university hospital. Twenty patients with incomplete cervical SCI who could stand without assistance were recruited. The floor and ceiling effects were evaluated by plotting histograms from the distribution of scores on the BBS, Mini-BESTest and Brief-BESTest, and calculating skewness. The Mini-BESTest and Brief-BESTest were evaluated and videotaped simultaneously, and intra- and inter-rater reliabilities were assessed. The MDC was also calculated. The skewness of the BBS was -1.57, and the full score was 35%, indicating a ceiling effect. However, no ceiling or floor effect was observed for the Mini-BESTest and the Brief-BESTest. Intraclass correlation coefficients for intra-rater and inter-rater reliabilities were 0.98 and 0.97 for the Mini-BESTest and Brief-BESTest, respectively. Individual item reliability was moderate or better for the Mini-BESTest and excellent or better for the Brief-BESTest. The MDC of total scores ranged 3.14-3.84 and 2.92-3.60 for the Mini-BESTest and Brief-BESTest, respectively. The Mini-BESTest and Brief-BESTest are reliable assessment tools for patients with acute and subacute incomplete SCI classified as AIS D. Clarified error ranges aid in estimating the treatment effect on balance abilities.

Anxiety and Depression after Spinal Cord Injury: A Cross-Sectional Study.

Spinal cord injury (SCI) is a life-changing event that often results in chronic physical damage and challenges in maintaining a good quality of life as it affects every aspect of life. These situations require adjustment, increasing vulnerability to psychological disorders. The objective of this study was to evaluate the impact of SCI on psychological morbidity in individuals with subacute and chronic SCI. The present investigation was designed to determine the presence and extent of psychological complications following SCI. We used two reliable questionnaires and validated psychological assessments to study depression (BDI) and anxiety (STAI), a broad range of factors derived from SCI that may be predictors of certain psychological problems. The psychological assessment revealed alterations in depression and anxiety, although the data do not exceed those of previous investigations. No clear predisposing factors leading to certain psychological pathologies were found. In addition, individuals in the subacute and chronic stages differed in their scores. In individuals with SCI, identifying predictors of psychological problems is difficult, but premature assessment of mental state is essential. This early diagnosis of possible problems or changes at the mental level is fundamental and necessary to avoid possible alterations at the cognitive level and, of course, more serious mental complications.

Extent of Traumatic Spinal Cord Injury Is Lesion Level Dependent and Predictive of Recovery: A Multicenter Neuroimaging Study.

Assessing the extent of the intramedullary lesion after spinal cord injury (SCI) might help to improve prognostication. However, because the neurological level of injury impacts the recovery potential of SCI patients, the question arises whether lesion size parameters and predictive models based on those parameters are affected as well. In this retrospective observational study, the extent of the intramedullary lesion between individuals who sustained cervical and thoracolumbar SCI was compared, and its relation to clinical recovery was assessed. In total, 154 patients with subacute SCI (89 individuals with cervical lesions and 65 individuals with thoracolumbar lesions) underwent conventional clinical magnetic resonance imaging 1 month after injury and clinical examination at 1 and 12 months. The morphology of the focal lesion within the spinal cord was manually assessed on the midsagittal slice of T2-weighted magnetic resonance images and compared between cervical and thoracolumbar SCI patients, as well as between patients who improved at least one American Spinal Injury Association Impairment Scale (AIS) grade (converters) and patients without AIS grade improvement (nonconverters). The predictive value of lesion parameters including lesion length, lesion width, and preserved tissue bridges for predicting AIS grade conversion was assessed using regression models (conditional inference tree analysis). Lesion length was two times longer in thoracolumbar compared with cervical SCI patients (F = 39.48, p < 0.0001), whereas lesion width and tissue bridges width did not differ. When comparing AIS grade converters and nonconverters, converters showed a smaller lesion length (F = 5.46, p = 0.021), a smaller lesion width (F = 13.75, p = 0.0003), and greater tissue bridges (F = 12.87, p = 0.0005). Using regression models, tissue bridges allowed more refined subgrouping of patients in AIS groups B, C, and D according to individual recovery profiles between 1 month and 12 months after SCI, whereas lesion length added no additional information for further subgrouping. This study characterizes differences in the anteroposterior and craniocaudal lesion extents after SCI. The two times greater lesion length in thoracolumbar compared with cervical SCI might be related to differences in the anatomy, biomechanics, and perfusion between the cervical and thoracic spines. Preserved tissue bridges were less influenced by the lesion level while closely related to the clinical impairment. These results highlight the robustness and utility of tissue bridges as a neuroimaging biomarker for predicting the clinical outcome after SCI in heterogeneous patient populations and for patient stratification in clinical trials.

Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial

ObjectiveNeurological and functional impairments are commonly observed in individuals with spinal cord injury (SCI) due to insufficient regeneration of damaged axons. Exosomes play a crucial role in the paracrine effects of mesenchymal stem cells (MSCs) and have emerged as a promising therapeutic approach for SCI. Thus, this study aimed to evaluate the safety and potential effects of intrathecal administration of allogeneic exosomes derived from human umbilical cord MSCs (HUC-MSCs) in patients with complete subacute SCI.MethodsThis study was a single-arm, open-label, phase I clinical trial with a 12-month follow-up period. HUC-MSCs were extracted from human umbilical cord tissue, and exosomes were isolated via ultracentrifugation. After intrathecal injection, each participant a underwent complete evaluation, including neurological assessment using the American Spinal Injury Association (ASIA) scale, functional assessment using the Spinal Cord Independence Measure (SCIM-III), neurogenic bowel dysfunction (NBD) assessment using the NBD score, modified Ashworth scale (MAS), and lower urinary tract function questionnaire.ResultsNine patients with complete subacute SCI were recruited. The intrathecal injection of allogeneic HUC-MSCs-exosomes was safe and well tolerated. No early or late adverse event (AE) attributable to the study intervention was observed. Significant improvements in ASIA pinprick (P-value = 0.039) and light touch (P-value = 0.038) scores, SCIM III total score (P-value = 0.027), and NBD score (P-value = 0.042) were also observed at 12-month after the injection compared with baseline.ConclusionsThis study demonstrated that intrathecal administration of allogeneic HUC-MSCs-exosomes is safe in patients with subacute SCI. Moreover, it seems that this therapy might be associated with potential clinical and functional improvements in these patients. In this regard, future larger phase II/III clinical trials with adequate power are highly required.Trial registrationIranian Registry of Clinical Trials, IRCT20200502047277N1. Registered 2 October 2020, https://en.irct.ir/trial/48765.

Hspb1 and Lgals3 in spinal neurons are closely associated with autophagy following excitotoxicity based on machine learning algorithms.

Excitotoxicity represents the primary cause of neuronal death following spinal cord injury (SCI). While autophagy plays a critical and intricate role in SCI, the specific mechanism underlying the relationship between excitotoxicity and autophagy in SCI has been largely overlooked. In this study, we isolated primary spinal cord neurons from neonatal rats and induced excitotoxic neuronal injury by high concentrations of glutamic acid, mimicking an excitotoxic injury model. Subsequently, we performed transcriptome sequencing. Leveraging machine learning algorithms, including weighted correlation network analysis (WGCNA), random forest analysis (RF), and least absolute shrinkage and selection operator analysis (LASSO), we conducted a comprehensive investigation into key genes associated with spinal cord neuron injury. We also utilized protein-protein interaction network (PPI) analysis to identify pivotal proteins regulating key gene expression and analyzed key genes from public datasets (GSE2599, GSE20907, GSE45006, and GSE174549). Our findings revealed that six genes-Anxa2, S100a10, Ccng1, Timp1, Hspb1, and Lgals3-were significantly upregulated not only in vitro in neurons subjected to excitotoxic injury but also in rats with subacute SCI. Furthermore, Hspb1 and Lgals3 were closely linked to neuronal autophagy induced by excitotoxicity. Our findings contribute to a better understanding of excitotoxicity and autophagy, offering potential targets and a theoretical foundation for SCI diagnosis and treatment.

Sex Dependent Disparities in the Central Innate Immune Response after Moderate Spinal Cord Contusion in Rat.

Subacute spinal cord injury (SCI) displays a complex pathophysiology associated with pro-inflammation and ensuing tissue damage. Microglia, the resident innate immune cells of the CNS, in concert with infiltrating macrophages, are the primary contributors to SCI-induced inflammation. However, subpopulations of activated microglia can also possess immunomodulatory activities that are essential for tissue remodeling and repair, including the production of anti-inflammatory cytokines and growth factors that are vital for SCI recovery. Recently, reports have provided convincing evidence that sex-dependent differences exist in how microglia function during CNS pathologies and the extent to which these cells contribute to neurorepair and endogenous recovery. Herein we employed flow cytometry and immunohistochemical methods to characterize the phenotype and population dynamics of activated innate immune cells within the injured spinal cord of age-matched male and female rats within the first week (7 days) following thoracic SCI contusion. This assessment included the analysis of pro- and anti-inflammatory markers, as well as the expression of critical immunomodulatory kinases, including P38 MAPK, and transcription factors, such as NFκB, which play pivotal roles in injury-induced inflammation. We demonstrate that activated microglia from the injured spinal cord of female rats exhibited a significantly diminutive pro-inflammatory response, but enhanced anti-inflammatory activity compared to males. These changes included lower levels of iNOS and TLR4 expression but increased levels of ARG-1 and CD68 in females after SCI. The altered expression of these markers is indicative of a disparate secretome between the microglia of males and females after SCI and that the female microglia possesses higher phagocytic capabilities (increased CD68). The examination of immunoregulatory kinases and transcription factors revealed that female microglia had higher levels of phosphorylated P38Thr180/Tyr182 MAPK and nuclear NFκB pp50Ser337 but lower amounts of nuclear NFκB pp65Ser536, suggestive of an attenuated pro-inflammatory phenotype in females compared to males after SCI. Collectively, this work provides novel insight into some of the sex disparities that exist in the innate immune response after SCI and indicates that sex is an important variable when designing and testing new therapeutic interventions or interpretating positive or negative responses to an intervention.

Defining malnutrition in persons with spinal cord injury - does the Global Criteria for Malnutrition work?

Physiologic and metabolic changes following spinal cord injury (SCI) lead to an increased risk of malnutrition. The Global Leadership Initiative on Malnutrition (GLIM) is a three-step approach to diagnose malnutrition: 1) screening; 2) phenotypic and etiological criteria; and 3) malnutrition severity. The main aim of this study was to assess malnutrition in patients with SCI, according to the GLIM criteria. Patients with SCI (≥ 18 years) admitted to rehabilitation were included. Anthropometrics, food intake, and inflammation were assessed on admission. Fat-free mass index (FFMI) was estimated from bioimpedance analysis. Malnutrition was diagnosed by the GLIM criteria, using the Malnutrition Universal Screening Tool (MUST) as the first step screening tool. Sensitivity and specificity analyses were performed. In total, 66 patients were assessed (50 men) with a mean age of 51.4 (± 17.4) years and median time since injury was 37.5 (10-450) days. The mean body mass index was 24.7 (± 4.2) kg/m2, and 1-month involuntary weight loss was 5.7 (± 4.4)%. FFMI for men was 17.3 (± 1.9) and for women 15.3 (± 1.6) kg/m2. Forty-one patients (62%) were malnourished according to the GLIM criteria: 27 moderately and 14 severely malnourished. MUST was not able to detect malnutrition risk of nine patients, giving a moderate agreement (kappa 0.66), with a sensitivity of 0.78 and a specificity of 0.92 compared to the GLIM diagnosis. In this cross-sectional study, 62% of subacute SCI patients were malnourished according to the GLIM criteria. The screening tool MUST showed moderate agreement with the GLIM criteria and did not detect risk of all patients with a malnutrition diagnosis. The clinical implications of these findings need further investigation.

Motor priming to enhance the effect of physical therapy in people with spinal cord injury

Context Brain–Computer Interface (BCI) is an emerging neurorehabilitation therapy for people with spinal cord injury (SCI). Objective The study aimed to test whether priming the sensorimotor system using BCI-controlled functional electrical stimulation (FES) before physical practice is more beneficial than physical practice alone. Methods Ten people with subacute SCI participated in a randomized control trial where the experimental (N = 5) group underwent BCI-FES priming (∼15 min) before physical practice (30 min), while the control (N = 5) group performed physical practice (40 min) of the dominant hand. The primary outcome measures were BCI accuracy, adherence, and perceived workload. The secondary outcome measures were manual muscle test, grip strength, the range of motion, and Electroencephalography (EEG) measured brain activity. Results The average BCI accuracy was 85%. The experimental group found BCI-FES priming mentally demanding but not frustrating. Two participants in the experimental group did not complete all sessions due to early discharge. There were no significant differences in physical outcomes between the groups. The ratio between eyes closed to eyes opened EEG activity increased more in the experimental group (theta Pθ = 0.008, low beta Plβ = 0.009, and high beta Phβ = 1.48e-04) indicating better neurological outcomes. There were no measurable immediate effects of BCI-FES priming. Conclusion Priming the brain before physical therapy is feasible but may require more than 15 min. This warrants further investigation with an increased sample size.

Patient Perceptions and Clinical Assessments of Cardiometabolic Disease After Subacute Spinal Cord Injury

ObjectivesTo investigate the effectiveness of health care team communication regarding cardiometabolic disease (CMD) risk factors with patients with subacute spinal cord injury (SCI). DesignMulti-site prospective cross-sectional study. SettingFive National Institute on Disability, Independent Living, and Rehabilitation Research Model SCI Rehabilitation Centers. ParticipantsNinety-six patients with subacute SCI, aged 18-70 years, with SCI (neurologic levels of injury C2-L2, American Spinal Injury Association Impairment Scale grades A-D), and enrolled within 2 months of initial rehabilitation discharge (N=96). InterventionsNone. Main Outcome Measure(s)Objective risk factors of CMD (body mass index, fasting glucose, insulin, high-density lipoprotein cholesterol, triglyceride levels, and resting blood pressure). Patient reported recall of these present risk factors being shared with them by their health care team. Medications prescribed to patients to address these present risk factors were checked against guideline- assessed risk factors. ResultsObjective evidence of 197 CMD risk factors was identified, with patients recalling less than 12% of these (P<.0001) being shared with them by their health care team. Thirty-one individuals (32%) met criteria for a diagnosis of CMD, with only 1 of these patients (3.2%) recalling that this was shared by their health care team (P<.0001). Pharmacologic management was prescribed to address these risk factors only 7.2% of the time. ConclusionsDespite high prevalence of CMD risk factors after acute SCI, patients routinely do not recall being told of their present risk factors. Multifaceted education and professionals’ engagement efforts are needed to optimize treatment for these individuals.

DiSCIoser: unlocking recovery potential of arm sensorimotor functions after spinal cord injury by promoting activity-dependent brain plasticity by means of brain-computer interface technology: a randomized controlled trial to test efficacy

BackgroundTraumatic cervical spinal cord injury (SCI) results in reduced sensorimotor abilities that strongly impact on the achievement of daily living activities involving hand/arm function. Among several technology-based rehabilitative approaches, Brain-Computer Interfaces (BCIs) which enable the modulation of electroencephalographic sensorimotor rhythms, are promising tools to promote the recovery of hand function after SCI. The “DiSCIoser” study proposes a BCI-supported motor imagery (MI) training to engage the sensorimotor system and thus facilitate the neuroplasticity to eventually optimize upper limb sensorimotor functional recovery in patients with SCI during the subacute phase, at the peak of brain and spinal plasticity. To this purpose, we have designed a BCI system fully compatible with a clinical setting whose efficacy in improving hand sensorimotor function outcomes in patients with traumatic cervical SCI will be assessed and compared to the hand MI training not supported by BCI.MethodsThis randomized controlled trial will include 30 participants with traumatic cervical SCI in the subacute phase randomly assigned to 2 intervention groups: the BCI-assisted hand MI training and the hand MI training not supported by BCI. Both interventions are delivered (3 weekly sessions; 12 weeks) as add-on to standard rehabilitation care. A multidimensional assessment will be performed at: randomization/pre-intervention and post-intervention. Primary outcome measure is the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) somatosensory sub-score. Secondary outcome measures include the motor and functional scores of the GRASSP and other clinical, neuropsychological, neurophysiological and neuroimaging measures.DiscussionWe expect the BCI-based intervention to promote meaningful cortical sensorimotor plasticity and eventually maximize recovery of arm functions in traumatic cervical subacute SCI. This study will generate a body of knowledge that is fundamental to drive optimization of BCI application in SCI as a top-down therapeutic intervention, thus beyond the canonical use of BCI as assistive tool.Trial registrationName of registry: DiSCIoser: improving arm sensorimotor functions after spinal cord injury via brain-computer interface training (DiSCIoser). Trial registration number: NCT05637775; registration date on the ClinicalTrial.gov platform: 05-12-2022.

Impact of Robotic-Assisted Gait Therapy on Depression and Anxiety Symptoms in Patients with Subacute Spinal Cord Injuries (SCIs)-A Prospective Clinical Study.

Mood disorders, especially depression, and emotional difficulties such as anxiety are very common problems among patients with spinal cord injuries (SCIs). The lack of physical training may deteriorate their mental state, which, in turn, has a significant impact on their improvement in functioning. The aim of the present study was to examine the influence of innovative rehabilitation approaches involving robotic-assisted gait therapy (RAGT) on the depression and anxiety symptoms in patients with SCI. A total of 110 participants with subacute SCIs were enrolled in this single-center, single-blinded, single-arm, prospective study; patients were divided into experimental (robotic-assisted gait therapy (RAGT)) and control (conventional gait therapy with dynamic parapodium (DPT)) groups. They received five training sessions per week over 7 weeks. At the beginning and end of therapy, the severity of depression was assessed via the Depression Assessment Questionnaire (KPD), and that of anxiety symptoms was assessed via the State-Trait Anxiety Inventory (STAI X-1). SCI patients in both groups experienced significantly lower levels of anxiety- and depression-related symptoms after completing the seven-week rehabilitation program (KPD: Z = 6.35, p < 0.001, r = 0.43; STAI X-1: Z = -6.20, p < 0.001, r = 0.42). In the RAGT group, post-rehabilitation measurements also indicated an improvement in psychological functioning (i.e., decreases in depression and anxiety and an increase in self-regulation (SR)). Significant results were noted for each variable (STAI X-1: Z = -4.93; KPD: Z = -5.26; SR: Z = -3.21). In the control group, there were also decreases in the effects on depression and state anxiety and an increase in self-regulation ability (STAI X-1: Z = -4.01; KPD: Z = -3.65; SR: Z = -2.83). The rehabilitation modality did not appear to have a statistically significant relationship with the magnitude of improvement in the Depression Assessment Questionnaire (KPD) (including self-regulation) and State-Trait Anxiety Inventory (STAI) scores. However, there were some significant differences when comparing the groups by the extent and depth of the injury and type of paralysis. Moreover, the study did not find any significant relationships between improvements in physical aspects and changes in psychological factors. Subjects in the robotic-assisted gait therapy (RAGD) and dynamic parapodium training (DPT) groups experienced decreases in anxiety and depression after a 7-week rehabilitation program. However, the rehabilitation modality (DPT vs. RAGT) did not differentiate between the patients with spinal cord injuries in terms of the magnitude of this change. Our results suggest that individuals with severe neurological conditions and complete spinal cord injuries (AIS A, according to the Abbreviated Injury Scale classification) may experience greater benefits in terms of changes in the psychological parameters after rehabilitation with RAGT.

Verification of the minimal clinically important difference of the Capabilities of Upper Extremity Test in patients with subacute spinal cord injury

Context The number of patients with cervical spinal cord injury (CSCI) is increasing, and the Capabilities of Upper Extremity Test (CUE-T) is recommended for introduction in clinical trials. We calculated the minimal clinically important difference (MCID) of the CUE-T using an adjustment model with an interval of 1 month. Design This was a prospective study. Setting This study was conducted with participants from the Chiba Rehabilitation Center in Japan. Participants The participants were patients with subacute CSCI. Interventions The CUE-T and spinal cord independence measure (SCIM) III were performed twice within an interval of 1 month. Outcome Measures The MCID was calculated using an adjustment model based on logistic regression analysis. The participants were classified into an improvement group and a non-improvement group based on the amount of change in the two evaluations using the 10-point SCIM III MCID as an anchor. Results There were 52 participants (56.8 ± 13.5 years old, 45 men/7 women) with complete or incomplete CSCI: 18 in the improvement group and 34 in the non-improvement group. A significant regression equation was obtained when calculating the MCID, and the total, hand, and side scores were 7.7, 2.0, and 3.7 points, respectively. Conclusion The calculated MCID of the CUE-T in this study was 7.7 points. The results of this study provide useful criteria for implementation in clinical trials. Future studies should use patient-reported outcomes, a more recommended anchor, and calculate the MCID using methods such as the patient’s condition.

Spasticity Predicts Motor Recovery for Patients with Subacute Motor Complete Spinal Cord Injury.

A motor complete spinal cord injury (SCI) results in the loss of voluntary motor control below the point of injury. Some of these patients can regain partial motor function through inpatient rehabilitation; however, there is currently no biomarker to easily identify which patients have this potential. Evidence indicates that spasticity could be that marker. Patients with motor complete SCI who exhibit spasticity show preservation of descending motor pathways, the pathways necessary for motor signals to be carried from the brain to the target muscle. We hypothesized that the presence of spasticity predicts motor recovery after subacute motor complete SCI. Spasticity (Modified Ashworth Scale and pendulum test) and descending connectivity (motor evoked potentials) were tested in the rectus femoris muscle in patients with subacute motor complete (n = 36) and motor incomplete (n = 30) SCI. Motor recovery was assessed by using the International Standards for Neurological Classification of Spinal Cord Injury and the American Spinal Injury Association Impairment Scale (AIS). All measurements were taken at admission and discharge from inpatient rehabilitation. We found that motor complete SCI patients with spasticity improved in motor scores and showed AIS conversion to either motor or sensory incomplete. Conversely, patients without spasticity showed no changes in motor scores and AIS conversion. In incomplete SCI patients, motor scores improved and AIS conversion occurred regardless of spasticity. These findings suggest that spasticity represents an easy-to-use clinical outcome that might help to predict motor recovery after severe SCI. This knowledge can improve inpatient rehabilitation effectiveness for motor complete SCI patients. ANN NEUROL 2023.

Intravenous Administration of Human Muse Cells Ameliorates Deficits in a Rat Model of Subacute Spinal Cord Injury.

Multilineage-differentiating stress-enduring (Muse) cells are newly established pluripotent stem cells. The aim of the present study was to examine the potential of the systemic administration of Muse cells as an effective treatment for subacute SCI. We intravenously administered the clinical product "CL2020" containing Muse cells to a rat model two weeks after mid-thoracic spinal cord contusion. Eight experimental animals received CL2020, and twelve received the vehicle. Behavioral analyses were conducted over 20 weeks. Histological evaluations were performed. After 20 weeks of observation, diphtheria toxin was administered to three CL2020-treated animals to selectively ablate human cell functions. Hindlimb motor functions significantly improved from 6 to 20 weeks after the administration of CL2020. The cystic cavity was smaller in the CL2020 group. Furthermore, larger numbers of descending 5-HT fibers were preserved in the distal spinal cord. Muse cells in CL2020 were considered to have differentiated into neuronal and neural cells in the injured spinal cord. Neuronal and neural cells were identified in the gray and white matter, respectively. Importantly, these effects were reversed by the selective ablation of human cells by diphtheria toxin. Intravenously administered Muse cells facilitated the therapeutic potential of CL2020 for severe subacute spinal cord injury.

Comparative Analysis of Cytokine Profiles in Cerebrospinal Fluid and Blood Serum in Patients with Acute and Subacute Spinal Cord Injury.

Cytokines are actively involved in the regulation of the inflammatory and immune responses and have crucial importance in the outcome of spinal cord injuries (SCIs). Examining more objective and representative indicators of the patient's condition is still required to reveal the fundamental patterns of the abovementioned posttraumatic processes, including the identification of changes in the expression of cytokines. We performed a dynamic (3, 7, and 14 days post-injury (dpi)) extended multiplex analysis of cytokine profiles in both CSF and blood serum of SCI patients with baseline American Spinal Injury Association Impairment Scale grades of A. The data obtained showed a large elevation of IL6 (>58 fold) in CSF and IFN-γ (>14 fold) in blood serum at 3 dpi with a downward trend as the post-traumatic period increases. The level of cytokine CCL26 was significantly elevated in both CSF and blood serum at 3 days post-SCI, while other cytokines did not show the same trend in the different biosamples. The dynamic changes in cytokine levels observed in our study can explore the relationships with the SCI region and injury severity, paving the way for a better understanding of the pathophysiology of SCI and potentially more targeted and personalized therapeutic interventions.

Identification of Differentially Expressed Proteins in Rats with Early Subacute Spinal Cord Injury using an iTRAQ-based Quantitative Analysis.

Injuries to the central nervous system (CNS), such as spinal cord injury (SCI), may devastate families and society. Subacute SCI may majorly impact secondary damage during the transitional period between the acute and subacute phases. A range of CNS illnesses has been linked to changes in the level of protein expression. However, the importance of proteins during the early subacute stage of SCI remains unknown. The role of proteins in the early subacute phase of SCI has not been established yet. SCI-induced damage in rats was studied using isobaric tagging for relative and absolute protein quantification (iTRAQ) to identify proteins that differed in expression 3 days after the injury, as well as proteins that did not alter in expression. Differentially expressed proteins (DEPs) were analyzed employing Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to discover the biological processes, cell components, and molecular functions of the proteins. We also performed Gene Set Enrichment Analysis (GSEA) software BP pathway and KEGG analysis on all proteins to further identify their functions. In addition, the first 15 key nodes of a protein-protein interaction (PPI) system were found. During the early subacute stage of SCI, we identified 176 DEPs in total between the control and damage groups, with 114 (64.77%) being up-regulated and 62 (35.23%) being downregulated. As a result of this study, we discovered the most important cellular components and molecular activities, as well as biological processes and pathways, in the early subacute phase of SCI. The top 15 high-degree core nodes were Alb, Plg, F2, Serpina1, Fgg, Apoa1, Vim, Hpx, Apoe, Agt, Ambp, Pcna, Gc, F12, and Gfap. Our study could provide new views on regulating the pathogenesis of proteins in the early subacute phase after SCI, which provides a theoretical basis for exploring more effective therapeutic targets for SCI in the future.

An Introduction to the North American Clinical Trials Network for Spinal Cord Injury Special Edition: Reflections on Accomplishments and a Look to the Future.

The North American Clinical Trials Network (NACTN) has been established as a network of translational clinical research centers focused on traumatic spinal cord injury (SCI) with the goals of facilitating clinical translational research, promotion of enhanced clinical care protocols including the principle of early surgery for SCI, and improving outcomes for individuals with acute SCI. Since its foundation in 2004 by Dr. Robert Grossman, NACTN has evolved into a powerful multi-stakeholder consortium of eight neurosurgical department faculties at university-affiliated institutions in the United States and Canada, a data management center, and a pharmacological center. To date, high-quality data from more than 1000 patients have been prospectively collected, providing us with a strong body of evidence surrounding SCI epidemiology, the natural history, and complications of acute and subacute SCI management. Key accomplishments of NACTN are summarized in this Focus issue. They include the launch, in collaboration with AO Spine, of the international, multi-center, placebo-controlled, Phase III Riluzole in Acute Spinal Cord Injury Study (RISCIS) that recruited 192 patients. While the primary analyses did not achieve the predetermined endpoint of efficacy for Riluzole, likely related to insufficient power, pre-planned secondary analyses demonstrated that all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with Riluzole showed significant gains in functional recovery. The Focus Issue also includes a detailed analysis of the pharmacokinetics and pharmacodynamics of riluzole in the setting of acute SCI (RISCIS-PK study). Additional achievements include key contributions to the evidence supporting the role of early surgery in acute SCI, and a better understanding of the impact of complications on the outcomes of SCI. Future directions of NACTN will build on past accomplishments and focus on enhanced collaborations with other SCI networks, advanced analytics to examine large datasets, and a greater focus on chronic SCI.

Impact of Robotic-Assisted Gait Training in Subacute Spinal Cord Injury Patients on Outcome Measure.

The improvement of walking ability is a primary goal for spinal cord injury (SCI) patients. Robotic-assisted gait training (RAGT) is an innovative method for its improvement. This study evaluates the influence of RAGT vs. dynamic parapodium training (DPT) in improving gait motor functions in SCI patients. In this single-centre, single-blinded study, we enrolled 105 (39 and 64 with complete and incomplete SCI, respectively) patients. The investigated subjects received gait training with RAGT (experimental S1-group) and DPT (control S0-group), with six training sessions per week over seven weeks. The American Spinal Cord Injury Association Impairment Scale Motor Score (MS), Spinal Cord Independence Measure, version-III (SCIM-III), Walking Index for Spinal Cord Injury, version-II (WISCI-II), and Barthel Index (BI) were assessed in each patient before and after sessions. Patients with incomplete SCI assigned to the S1 rehabilitation group achieved more significant improvement in MS [2.58 (SE 1.21, p < 0.05)] and WISCI-II [3.07 (SE 1.02, p < 0.01])] scores in comparison with patients assigned to the S0 group. Despite the described improvement in the MS motor score, no progression between grades of AIS (A to B to C to D) was observed. A nonsignificant improvement between the groups for SCIM-III and BI was found. RAGT significantly improved gait functional parameters in SCI patients in comparison with conventional gait training with DPT. RAGT is a valid treatment option in SCI patients in the subacute phase. DPT should not be recommended for patients with incomplete SCI (AIS-C); in those patients, RAGT rehabilitation programs should be taken into consideration.