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Catherine R Jutzeler,1–3 Freda M Warner,1,2 Jacquelyn J Cragg,1,3 Jenny Haefeli,4 J Scott Richards,5 Sven R Andresen,6 Nanna B Finnerup,7,8 Catherine Mercier,9 John LK Kramer1,2 1Faculty of Medicine, ICORD, University of British Columbia, Vancouver, BC, Canada; 2Faculty of Education, School of Kinesiology, University of BC, Vancouver, BC, Canada; 3Faculty of Medicine, Spinal Cord Injury Center, University Hospital Balgrist, University of Zurich, Zurich, Switzerland; 4Weill Institute for Neurosciences, Department of Neurological Surgery, Brain and Spinal Injury Center, University of California, San Francisco, CA, USA; 5Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, USA; 6Spinal Cord Injury Centre of Western Denmark, Department of Neurology, Regional Hospital of Viborg, Viborg, Denmark; 7Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 8Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 9Center for Interdisciplinary Research in Rehabilitation and Social Integration, Québec, QC, Canada Background: Understanding factors associated with high placebo responses in clinical trials increases the likelihood of detecting a meaningful treatment effect. The aim of the present study was to identify subject-level factors that contribute to placebo variability in patients with neuropathic pain due to spinal cord injury (SCI).Methods: Multiple regression analysis of patient data from randomized, double-blind, placebo-controlled trials (duration >4 weeks) involving individuals with SCI was performed. Patient demographics, as well as injury and pain characteristics were examined for their association with changes in pain rating from baseline to the end of the trial (i.e., placebo response). The overall effect of individual predictors was quantified with meta-analysis statistics.Results: A total of 276 patients with SCI from six studies were included in the analysis. Based on the meta-analysis of subject-level predictors, larger placebo responses were associated with male subjects (β=0.635; standard error [SE]=0.262; p=0.016) and higher baseline pain (β=−0.146; SE=0.073; p=0.044). There were no significant effects for injury characteristics (i.e., severity, level, and time since injury) or pain characteristics (i.e., location and evoked). No significant publication bias was detected.Conclusion: The current meta-analysis of individual patient data demonstrated the importance of sex and baseline pain intensity on changes in pain ratings in the placebo arm of SCI central neuropathic pain randomized controlled clinical trials. Overall, our findings indicate that placebo responses occur independent of injury characteristics. Keywords: placebo response, clinical trial, spinal cord injury, neuropathic pain

BackgroundPredicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients.MethodsIntra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods.ResultsNetwork analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery.ConclusionsWe show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention.FundingNIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).

Background and purposeAcute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment.Materials and methodsWe performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment.ResultsNonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression.ConclusionsThis study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging.

Following nociceptive heat or laser stimulation, an early contralateral and later vertex potential can be recorded. Although more indicative of the nociceptive input, the acquisition of the contralateral N1 after contact heat stimulation (contact heat-evoked potentials [CHEPs]) remains difficult. An advantage of contact heat is that the baseline skin temperature preceding peak stimulation can be controlled. Increasing the baseline temperature may represent a novel strategy to improve the acquisition of CHEPs without resulting in more subjective pain to stimulation. A study was undertaken in 23 healthy subjects to examine the effects of increasing the baseline temperature but not the perceived intensity of contact heat stimulation. A combined standard averaging and single-trial analysis was performed to disclose how changes in averaged waveforms related to latency jitter and individual trial amplitudes. By increasing the baseline temperature, the acquisition of N1 was improved among subjects with a low-amplitude response (greater than -4μV) following 35°C baseline temperature stimulation (P<.05). Based on standard averaging, N2/P2 amplitudes were also significantly increased with and without an accompanying change in the rating of perceived pain when the baseline temperature was increased (P<.05). In contrast, automated single-trial averaging revealed no significant difference in N2 amplitude when the baseline temperature was increased to 42°C and the peak temperature reduced. These findings suggest that 2 mechanisms underlie the improved acquisition of CHEPs: increased synchronization of afferent volley, yielding larger-amplitude evoked potentials in response to the same rating of intensity; and reduced inter-trial variability. [ABSTRACT FROM AUTHOR]

Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients., Methods: Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods., Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery., Conclusions: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention., Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB)., Competing Interests: AT, JH, RE, DT, CA, JH, AC, DM, NS, BD, CS, JN, NK, DH, JT, GM, SD, WW, JB, MB, SM, JP, AF No competing interests declared, (© 2021, Torres-Espín et al.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Aims of the Study: Atezolizumab is an approved therapy for urothelial carcinoma based on results from the IMvigor 210 and IMvigor211 phase II and III trials. The global SAUL study evaluated atezolizumab in a broader patient population more representative of real-world populations. Among approximately 1000 patients treated in SAUL, 25 were treated in Swiss oncology centres. We evaluated outcomes in these patients to provide a better understanding of atezolizumab treatment for urinary tract carcinoma in Swiss clinical practice., Methods: Eligible patients had locally advanced or metastatic urothelial or non-urothelial urinary tract carcinoma that had progressed during or after one to three prior therapies for inoperable, locally advanced or metastatic disease. Patient populations typically excluded from clinical trials (e.g., patients with renal impairment, treated central nervous system [CNS] metastases, stable controlled autoimmune disease or Eastern Cooperative Oncology Group performance status 2) were also eligible. All patients received atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included overall survival (OS), overall response rate (ORR) and disease control rate (DCR)., Results: All 25 Swiss patients had previously received a gemcitabine/platinum doublet. Disease had progressed within 12 months of platinum-based therapy in all but one patient, and 19 (76%) had received one prior line of therapy for metastatic disease. The median duration of atezolizumab therapy was six cycles (range 1&ndash;27) corresponding to 3.6 months. Five patients (20%) had received &gt;20 cycles and four (16%) remained on treatment at the data cut-off. Grade 3 adverse events (AEs) occurred in 13 patients (52%) and were considered to be treatment-related in four patients (16%; liver enzyme increases, musculoskeletal pain, diverticulitis and autoimmune hepatitis). There was one grade 4 AE (hypercalcaemia) and no grade 5 AEs. After median follow-up of 17.3 months, median OS was 7.9 months (95% confidence interval [CI] 5.3&ndash;not evaluable), the 1-year OS rate was 47% (95% CI 27&ndash;65%), the ORR was 12% (95% CI 3&ndash;31%) and the DCR was 40% (95% CI 21&ndash;61%). Durable clinical benefit (&gt;1 year on treatment) was observed in seven patients (28%), including one with CNS metastases and one with small-cell carcinoma., Conclusions: Atezolizumab is an active treatment option for platinum-pretreated urinary tract carcinoma, including patients with conditions that typically exclude them from clinical trials. (Trial registration no.: NCT02928406).

Objective: Traumatic spinal cord injury (SCI) is a dreaded condition that can lead to paralysis and severe disability. With few treatment options available for patients who have suffered from SCI, it is important to develop prospective databases to standardize data collection in order to develop new therapeutic approaches and guidelines. Here, the authors present an overview of their multicenter, prospective, observational patient registry, Transforming Research and Clinical Knowledge in SCI (TRACK-SCI)., Methods: Data were collected using the National Institute of Neurological Disorders and Stroke (NINDS) common data elements (CDEs). Highly granular clinical information, in addition to standardized imaging, biospecimen, and follow-up data, were included in the registry. Surgical approaches were determined by the surgeon treating each patient; however, they were carefully documented and compared within and across study sites. Follow-up visits were scheduled for 6 and 12 months after injury., Results: One hundred sixty patients were enrolled in the TRACK-SCI study. In this overview, basic clinical, imaging, neurological severity, and follow-up data on these patients are presented. Overall, 78.8% of the patients were determined to be surgical candidates and underwent spinal decompression and/or stabilization. Follow-up rates to date at 6 and 12 months are 45% and 36.3%, respectively. Overall resources required for clinical research coordination are also discussed., Conclusions: The authors established the feasibility of SCI CDE implementation in a multicenter, prospective observational study. Through the application of standardized SCI CDEs and expansion of future multicenter collaborations, they hope to advance SCI research and improve treatment.

Study Design: Retrospective analysis., Objective: To assess the impact of mean arterial blood pressure (MAP) during surgical intervention for spinal cord injury (SCI) on motor recovery., Setting: Level-one Trauma Hospital and Acute Rehabilitation Hospital in San Jose, CA, USA., Methods: Twenty-five individuals with traumatic SCI who received surgical and acute rehabilitation care at a level-one trauma center were included in this study. The Surgical Information System captured intraoperative MAPs on a minute-by-minute basis and exposure was quantified at sequential thresholds from 50 to 104 mmHg. Change in International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score was calculated based on physiatry evaluations at the earliest postoperative time and at discharge from acute rehabilitation. Linear regression models were used to estimate the rate of recovery across the entire MAP range., Results: An exploratory analysis revealed that increased time within an intraoperative MAP range (70-94 mmHg) was associated with ISNCSCI motor score improvement. A significant regression equation was found for the MAP range 70-94 mmHg (F[1, 23] = 5.07, r 2  = 0.181, p = 0.034). ISNCSCI motor scores increased 0.039 for each minute of exposure to the MAP range 70-94 mmHg during the operative procedure; this represents a significant correlation between intraoperative time with MAP 70-94 and subsequent motor recovery. Blood pressure exposures above or below this range did not display a positive association with motor recovery., Conclusions: Hypertension as well as hypotension during surgery may impact the trajectory of recovery in individuals with SCI, and there may be a direct relationship between intraoperative MAP and motor recovery.

The sensitizing effect of capsaicin has been previously characterized using laser and contact heat evoked potentials (LEPs and CHEPs) by stimulating in the primary area of hyperalgesia. Interestingly, only CHEPs reveal changes consistent with notion of peripheral sensitization (i.e., reduced latencies). The aim of this study was to investigate contact heat stimulation parameters necessary to detect peripheral sensitization related to the topical application of capsaicin, and therefore significantly improve the current method of measuring peripheral sensitization via CHEPs. Rapid contact heat stimulation (70°C/s) was applied from three different baseline temperatures (35, 38.5, and 42°C) to a 52°C peak temperature, before and after the topical application of capsaicin on the hand dorsum. Increased pain ratings in the primary area of hyperalgesia were accompanied by reduced N2 latency. Changes in N2 latency were, however, only significant following stimulation from 35 and 38.5°C baseline temperatures. These findings suggest that earlier recruitment of capsaicin-sensitized afferents occurs between 35 and 42°C, as stimulations from 42°C baseline were unchanged by capsaicin. This is in line with reduced thresholds of type II A-delta mechanoheat (AMH) nociceptors following sensitization. Conventional CHEP stimulation, with a baseline temperature below 42°C, is well suited to objectively detect evidence of peripheral sensitization., (Copyright © 2020 Linde, Haefeli, Jutzeler, Rosner, McDougall, Curt and Kramer.)

Background: Cervical spinal cord injury (SCI) is a devastating condition with very few treatment options. It remains unclear if early surgery correlated with conversion of American Spinal Injury Association Impairment Scale (AIS) grade A injuries to higher grades., Objective: To determine the optimal time to surgery after cervical SCI through retrospective analysis., Methods: We collected data from 48 patients with cervical SCI. Based on the time from Emergency Department (ED) presentation to surgical decompression, we grouped patients into ultra-early (decompression within 12 h of presentation), early (within 12-24 h), and late groups (>24 h). We compared the improvement in AIS grade from admission to discharge, controlling for confounding factors such as AIS grade on admission, injury severity, and age. The mean time from injury to ED for this group of patients was 17 min., Results: Patients who received surgery within 12 h after presentation had a relative improvement in AIS grade from admission to discharge: the ultra-early group improved on average 1.3. AIS grades compared to 0.5 in the early group (P = .02). In addition, 88.8% of patients with an AIS grade A converted to a higher grade (AIS B or better) in the ultra-early group, compared to 38.4% in the early and late groups (P = .054)., Conclusion: These data suggest that surgical decompression after SCI that takes place within 12 h may lead to a relative improved neurological recovery compared to surgery that takes place after 12 h., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Background: While the utilization of neurophysiologic intraoperative monitoring with motor evoked potentials (MEPs) has become widespread in surgery for traumatic spine fractures and spinal cord injury (SCI), clinical validation of its diagnostic and therapeutic benefit has been limited., Objective: To describe the use of intraoperative MEP at a large level I trauma center and assess the prognostic capability of this technology., Methods: The SCI REDCap database at our institution, a level I trauma center, was queried for acute cervical SCI patients who underwent surgery with intraoperative monitoring between 2005 and 2011, yielding 32 patients. Of these, 23 patients had severe SCI (association impairment scale [AIS] A, B, C). We assessed preoperative and postoperative SCI severity (AIS grade), surgical data, use of steroids, and early magnetic resonance imaging (MRI) findings (preoperatively in 27 patients), including axial T2 MRI grade (Brain and Spinal Injury Center score)., Results: The presence of MEPs significantly predicted AIS at discharge (P< .001). In the group of severe SCI (ie, AIS A, B, C) patients with elicitable MEPs, AIS improved by an average of 1.5 grades (median = 1), as compared to the patients without elicitable MEP who improved on average 0.5 grades (median = 0, P< .05). In addition, axial MRI grade significantly correlated with MEP status. Patients without MEPs had a significantly higher axial MRI grade in comparison to the patients with MEPs (P< .001)., Conclusion: In patients with severe SCI, MEPs predicted neurological improvement and correlated with axial MRI grade. These significant findings warrant future prospective studies of MEPs as a prognostic tool in SCI.

Purpose: To couple quantitative compositional MRI, gait analysis, and machine learning multidimensional data analysis to study osteoarthritis (OA). OA is a multifactorial disorder accompanied by biochemical and morphological changes in the articular cartilage, modulated by skeletal biomechanics and gait. While we can now acquire detailed information about the knee joint structure and function, we are not yet able to leverage the multifactorial factors for diagnosis and disease management of knee OA., Materials and Methods: We mapped 178 subjects in a multidimensional space integrating: demographic, clinical information, gait kinematics and kinetics, cartilage compositional T 1ρ and T 2 and R 2 -R 1ρ (1/T 2 -1/T 1ρ ) acquired at 3T and whole-organ magnetic resonance imaging score morphological grading. Topological data analysis (TDA) and Kolmogorov-Smirnov test were adopted for data integration, analysis, and hypothesis generation. Regression models were used for hypothesis testing., Results: The results of the TDA showed a network composed of three main patient subpopulations, thus potentially identifying new phenotypes. T 2 and T 1ρ values (T 2 lateral femur P = 1.45*10 -8 , T 1ρ medial tibia P = 1.05*10 -5 ), the presence of femoral cartilage defects (P = 0.0013), lesions in the meniscus body (P = 0.0035), and race (P = 2.44*10 -4 ) were key markers in the subpopulation classification. Within one of the subpopulations we observed an association between the composite metric R 2 -R 1ρ and the longitudinal progression of cartilage lesions., Conclusion: The analysis presented demonstrates some of the complex multitissue biochemical and biomechanical interactions that define joint degeneration and OA using a multidimensional approach, and potentially indicates that R 2 -R 1ρ may be an imaging biomarker for early OA., Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:78-90., (© 2017 International Society for Magnetic Resonance in Medicine.)

OBJECTIVE Spinal cord injuries (SCIs) occur in approximately 17,000 people in the US each year. The average length of hospital stay is 11 days, and deep venous thrombosis (DVT) rates as high as 65% are reported in these patients. There is no consensus on the appropriate timing of chemical DVT prophylaxis for this critically injured patient cohort. The object of this study was to determine if low-molecular-weight heparin (LMWH) was safe and effective if given within 24 hours of SCI. METHODS The Transforming Research and Clinical Knowledge in SCIs study is a prospective observational study conducted by the UCSF Brain and Spinal Injury Center. Protocol at this center includes administration of LMWH within 24 hours of SCI. Data were retrospectively reviewed to determine DVT rate, pulmonary embolism (PE) rate, and hemorrhagic complications. RESULTS Forty-nine patients were enrolled in the study. There were 3 DVTs (6.1%), 2 PEs (4.1%), and no hemorrhagic complications. Regression modeling did not find an association between DVT and/or PE and age, American Spinal Injury Association grade, sex, race, or having undergone a neurosurgical procedure. CONCLUSIONS A standardized protocol in which LMWH is given to patients with SCI within 24 hours of injury is effective in keeping venous thromboembolism at the lower end of the reported range, and is safe, with a zero rate of adverse bleeding events.

Spinal cord injury (SCI) is a multifaceted phenomenon associated with alterations in both motor function and sensory function. A majority of patients with SCI report sensory disturbances, including not only loss of sensation, but in many cases enhanced abnormal sensation, dysesthesia and pain. Development of therapeutics to treat these abnormal sensory changes require common measurement tools that can enable cross-species translation from animal models to human patients. We review the current literature on translational nociception/pain measurement in SCI and discuss areas for further development. Although a number of tools exist for measuring both segmental and affective sensory changes, we conclude that there is a pressing need for better, integrative measurement of nociception/pain outcomes across species to enhance precise therapeutic innovation for sensory dysfunction in SCI., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Spinal cord injury (SCI) is a devastating syndrome that produces dysfunction in motor and sensory systems, manifesting as chronic paralysis, sensory changes, and pain disorders. The multi-faceted and heterogeneous nature of SCI has made effective rehabilitative strategies challenging. Work over the last 40 years has aimed to overcome these obstacles by harnessing the intrinsic plasticity of the spinal cord to improve functional locomotor recovery. Intensive training after SCI facilitates lower extremity function and has shown promise as a tool for retraining the spinal cord by engaging innate locomotor circuitry in the lumbar cord. As new training paradigms evolve, the importance of appropriate afferent input has emerged as a requirement for adaptive plasticity. The integration of kinematic, sensory, and loading force information must be closely monitored and carefully manipulated to optimize training outcomes. Inappropriate peripheral input may produce lasting maladaptive sensory and motor effects, such as central pain and spasticity. Thus, it is important to closely consider the type of afferent input the injured spinal cord receives. Here we review preclinical and clinical input parameters fostering adaptive plasticity, as well as those producing maladaptive plasticity that may undermine neurorehabilitative efforts. We differentiate between passive (hindlimb unloading [HU], limb immobilization) and active (peripheral nociception) forms of aberrant input. Furthermore, we discuss the timing of initiating exposure to afferent input after SCI for promoting functional locomotor recovery. We conclude by presenting a candidate rapid synaptic mechanism for maladaptive plasticity after SCI, offering a pharmacological target for restoring the capacity for adaptive spinal plasticity in real time.

Background and Purpose: Acute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment., Materials and Methods: We performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment., Results: Nonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression., Conclusions: This study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging., (© 2017 by American Journal of Neuroradiology.)

Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with combinations of an anti-inflammatory agent (minocycline), a neurotrophic agent (LM11A-31), and physical therapy consisting of assisted exercise with or without botulinum toxin-induced limb constraint. Data was curated and analyzed in a linked workflow involving non-linear principal component analysis followed by hypothesis testing with a linear mixed model. Results revealed significant benefits of the neurotrophic agent LM11A-31 on learning and memory outcomes after traumatic brain injury. In addition, modulations of LM11A-31 effects by co-administration of minocycline and by the type of physical therapy applied reached statistical significance. These results suggest a combinatorial effect of drug and physical therapy interventions that was not evident by univariate analysis. The study designs and analytic techniques applied here form a structured, unbiased, internally validated workflow that may be applied to other combinatorial studies, both in animals and humans.

Background Approximately 60% of patients suffering from acute spinal cord injury (SCI) develop pain within days to weeks after injury, which ultimately persists into chronic stages. To date, the consequences of pain after SCI have been largely examined in terms of interfering with quality of life. Objective The objective of this study was to examine the effects of pain and pain management on neurological recovery after SCI. Methods We analyzed clinical data in a prospective multicenter observational cohort study in patients with SCI. Using mixed effects regression techniques, total motor and sensory scores were modelled at 1, 3, 6, and 12 months postinjury. Results A total of 225 individuals were included in the study (mean age: 45.8 ± 18 years, 80% male). At 1 month postinjury, 28% of individuals with SCI reported at- or below-level neuropathic pain. While pain classification showed no effect on neurological outcomes, individuals administered anticonvulsant medications at 1 month postinjury showed significant reductions in pain intensity (2 points over 1 year; P < .05) and greater recovery in total motor scores (7.3 points over 1 year; P < .05). This drug effect on motor recovery remained significant after adjustment for injury level and injury severity, pain classification, and pain intensity. Conclusion While initial pain classification and intensity did not reveal an effect on motor recovery following acute SCI, anticonvulsants conferred a significant beneficial effect on motor outcomes. Early intervention with anticonvulsants may have effects beyond pain management and warrant further studies to evaluate the therapeutic effectiveness in human SCI., (© The Author(s) 2016.)

Literature examining magnetic resonance imaging (MRI) in acute spinal cord injury (SCI) has focused on cervical SCI. Reproducible systems have been developed for MRI-based grading; however, it is unclear how they apply to thoracic SCI. Our hypothesis is that MRI measures will group as coherent multivariate principal component (PC) ensembles, and that distinct PCs and individual variables will show discriminant validity for predicting early impairment in thoracic SCI. We undertook a retrospective cohort study of 25 patients with acute thoracic SCI who underwent MRI on admission and had American Spinal Injury Association Impairment Scale (AIS) assessment at hospital discharge. Imaging variables of axial grade, sagittal grade, length of injury, thoracolumbar injury classification system (TLICS), maximum canal compromise (MCC), and maximum spinal cord compression (MSCC) were collected. We performed an analytical workflow to detect multivariate PC patterns followed by explicit hypothesis testing to predict AIS at discharge. All imaging variables loaded positively on PC1 (64.3% of variance), which was highly related to AIS at discharge. MCC, MSCC, and TLICS also loaded positively on PC2 (22.7% of variance), while variables concerning cord signal abnormality loaded negatively on PC2. PC2 was highly related to the patient undergoing surgical decompression. Variables of signal abnormality were all negatively correlated with AIS at discharge with the highest level of correlation for axial grade as assessed with the Brain and Spinal Injury Center (BASIC) score. A multiple variable model identified BASIC as the only statistically significant predictor of AIS at discharge, signifying that BASIC best captured the variance in AIS within our study population. Our study provides evidence of convergent validity, construct validity, and clinical predictive validity for the sampled MRI measures of SCI when applied in acute thoracic and thoracolumbar SCI.

The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animal's spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies.

Recent preclinical advances highlight the therapeutic potential of treatments aimed at boosting regeneration and plasticity of spinal circuitry damaged by spinal cord injury (SCI). With several promising candidates being considered for translation into clinical trials, the SCI community has called for a non-human primate model as a crucial validation step to test efficacy and validity of these therapies prior to human testing. The present paper reviews the previous and ongoing efforts of the California Spinal Cord Consortium (CSCC), a multidisciplinary team of experts from 5 University of California medical and research centers, to develop this crucial translational SCI model. We focus on the growing volumes of high resolution data collected by the CSCC, and our efforts to develop a biomedical informatics framework aimed at leveraging multidimensional data to monitor plasticity and repair targeting recovery of hand and arm function. Although the main focus of many researchers is the restoration of voluntary motor control, we also describe our ongoing efforts to add assessments of sensory function, including pain, vital signs during surgery, and recovery of bladder and bowel function. By pooling our multidimensional data resources and building a unified database infrastructure for this clinically relevant translational model of SCI, we are now in a unique position to test promising therapeutic strategies' efficacy on the entire syndrome of SCI. We review analyses highlighting the intersection between motor, sensory, autonomic and pathological contributions to the overall restoration of function. This article is part of a Special Issue entitled SI: Spinal cord injury., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background Although a mainstay of clinical sensory examination after damage in the spinal cord, pinprick sensation represents only one afferent modality conveyed in the spinothalamic tract. As an objective outcome, complementary information regarding spinothalamic tract conduction may be elucidated by measuring contact heat evoked potentials (CHEPs). Objective To assess the value of CHEPs to measure spinothalamic tract function in spinal cord disorders compared with pinprick scoring. Methods CHEPs were examined using a standard (35°C) and increased baseline (42°C) contact heat temperature. Pinprick sensation was rated as absent, impaired, or normal according to the International Standards for the Neurological Classification of Spinal Cord Injury. Results Fifty-nine dermatomes above, at, and below the sensory level of impairment were analyzed in 37 patients with defined spinal cord disorder. In dermatomes with absent or impaired pinprick sensation, CHEPs using a standard baseline temperature were mainly abolished (3/16 and 8/35, respectively). However, when applying an increased baseline temperature, CHEPs became recordable (absent: 11/16; impaired: 31/35). Furthermore, CHEPs with increased baseline temperature allowed discerning between dermatomes with absent, impaired, and normal pinprick sensation when using an objective measure (ie, N2P2 amplitude). In contrast, the pain perception to contact heat stimulation was independent of pinprick scores. Conclusion Applying pinprick testing is of limited sensitivity to assess spinothalamic tract function in spinal cord disorders. The application of CHEPs (using standard and increased baseline temperatures) as an objective readout provides complementary information of spinothalamic tract functional integrity beyond pinprick testing., (© The Author(s) 2013.)

Imaging studies have identified a wide network of brain areas activated by nociceptive stimuli and revealed differences in somatotopic representation of highly distinct stimulation sites (foot vs. hand) in the primary (S1) and secondary (S2) somatosensory cortices. Somatotopic organization between adjacent dermatomes and differences in cortical coding of similarly perceived nociceptive stimulation are less well studied. Here, cortical processing following contact heat nociceptive stimulation of cervical (C4, C6, and C8) and trunk (T10) dermatomes were recorded in 20 healthy subjects using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Stimulation of T10 compared with the C6 and C8 revealed significant higher response intensity in the left S1 (contralateral) and the right S2 (ipsilateral) even when the perceived pain was equal between stimulation sites. Accordingly, contact heat evoked potentials following stimulation of T10 showed significantly higher N2P2 amplitudes compared to C6 and C8. Adjacent dermatomes did not reveal a distinct somatotopical representation. Within the assessed cervical and trunk dermatomes, nociceptive cortical processing to heat differs significantly in magnitude even when controlling for pain perception. This study provides evidence that controlling for pain perception is not sufficient to compare directly the magnitude of cortical processing [blood oxygen level dependence (BOLD) response and amplitude of evoked potentials] between body sites., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: To evaluate the sensitivity of contact heat evoked potentials (CHEPs) compared with dermatomal somatosensory evoked potentials (dSSEPs) and clinical sensory testing in myelopathic spinal cord disorders (SCDs)., Methods: In a prospective cohort study, light-touch (LT) and pinprick (PP) testing was complemented by dermatomal CHEPs and dSSEPs in patients with a confirmed SCD as defined by MRI. Patients with different etiologies (i.e., traumatic and nontraumatic) and varying degrees of spinal cord damage (i.e., completeness) were included. SCD was distinguished into 3 categories according to MRI pattern and neurologic examination: a) complete, b) incomplete-diffuse, and c) central or anterior cord damage., Results: Seventy-five patients were included (complete n = 7, incomplete-diffuse n = 33, central/anterior n = 35). In total, 319 dermatomes were tested with combined CHEPs and dSSEPs. CHEPs, dSSEPs, and clinical sensory testing were comparably sensitive to detect the myelopathy in complete (CHEPs 100%, dSSEPs 91%, PP and LT 82%) and incomplete-diffuse (CHEPs 92%, dSSEPs and PP 86%, LT 81%, p > 0.05 for all comparisons) cord damage. In central/anterior cord damage, CHEPs showed a significantly higher sensitivity than dSSEPs (89% compared with 24%, p < 0.001) and clinical sensory testing (PP 62%, LT 57%, p < 0.05). A subclinical sensory impairment was detected more frequently by CHEPs than dSSEPs (60% compared with 29%, p = 0.001)., Conclusions: Assessment of spinothalamic pathways with CHEPs is reliable and revealed the highest sensitivity in all SCDs. Specifically in incomplete lesions that spare dorsal pathways, CHEPs are sensitive to complement the clinical diagnosis.

Sensory input from the periphery to the brain can be severely compromised or completely abolished after an injury to the spinal cord. Evidence from animal models suggests that endogenous repair processes in the spinal cord mediate extensive sprouting and that this might be further attenuated by targeted therapeutic interventions. However, the extent to which sprouting can contribute to spontaneous recovery after human spinal cord injury (SCI) remains largely unknown, in part because few measurement tools are available in order to non-invasively detect subtle changes in neurophysiology. The proposed application of segmental sensory evoked potentials (e.g., dermatomal contact heat evoked potentials and somatosensory evoked potentials) to assess conduction in ascending pathways (i.e., spinothalamic and dorsal column, respectively) differs from conventional approaches in that individual spinal segments adjacent to the level of lesion are examined. The adoption of these approaches into clinical research might provide improved resolution for measuring changes in sensory impairments and might determine the extent by which spontaneous recovery after SCI is mediated by similar endogenous repair mechanisms in humans as in animal models.

This study investigated the interactions of supraspinal with spinal neuronal circuits during obstacle steps by recordings of electroencephalography (EEG), reflex activity and limb muscle electromyography (EMG). Subjects walking with reduced vision on a treadmill were acoustically informed about an approaching obstacle and received feedback about task performance. Only following a task-relevant acoustic signal, spinal reflex responses, evoked by tibial nerve stimulation during mid-stance, were enhanced in proximal arm and leg flexor muscles prior to obstacle compared to normal swing, reflecting the neuronal preparation of the task. During swing over the obstacle, limb muscle EMG activity was greater than in normal swing. Both the preparation and the performance (i.e. ascending movement slope of the obstacle-crossing leg) were associated with an enhanced EEG signal mainly in the prefrontal cortex of the right hemisphere. Adaptational changes in performance, reflex activity and muscle activation during repetitive obstacle stepping were not reflected in the EEG activity, probably due to an insufficient resolution of the EEG. The observations suggest that drive from supraspinal centers initiates and maintains spinal neuronal activity underlying obstacle task preparation and performance., (© 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)