Evaluating peripheral neuromuscular function with brief movement-evoked pain.

Movement-evoked pain is an understudied manifestation of musculoskeletal conditions that contributes to disability, yet little is known about how the neuromuscular system responds to movement-evoked pain. The present study examined whether movement-evoked pain impacts force production, electromyographic (EMG) muscle activity, and the rate of force development (RFD) during submaximal muscle contractions. Fifteen healthy adults (9 males; age = 30.3 ± 10.2 yr, range = 22-59 yr) performed submaximal isometric first finger abduction contractions without pain (baseline) and with movement-evoked pain induced by laser stimulation to the dorsum of the hand. Normalized force (% maximal voluntary contraction) and RFD decreased by 11% (P < 0.001) and 15% (P = 0.003), respectively, with movement-evoked pain, without any change in normalized peak EMG (P = 0.77). Early contractile RFD, force impulse, and corresponding EMG amplitude computed within time segments of 50, 100, 150, and 200 ms relative to the onset of movement were also unaffected by movement-evoked pain (P > 0.05). Our results demonstrate that movement-evoked pain impairs peak characteristics and not early measures of submaximal force production and RFD, without affecting EMG activity (peak and early). Possible explanations for the stability in EMG with reduced force include antagonist coactivation and a reorganization of motoneuronal activation strategy, which is discussed here.NEW & NOTEWORTHY We provide neurophysiological evidence to indicate that peak force and rate of force development are reduced by movement-evoked pain despite a lack of change in EMG and early rapid force development in the first dorsal interosseous muscle. Additional evidence suggests that these findings may coexist with a reorganization in motoneuronal activation strategy.

A Comparison of Neuropathic Pain Experiences Among Paralympic Versus Recreational Athletes with Spinal Cord Injury.

BACKGROUND: Individuals with spinal cord injury (SCI) report high levels of neuropathic pain. Current treatment options are primarily pharmaceutical, despite their limited effectiveness. Exercise may reduce neuropathic pain among persons with SCI; however, the optimal dose of exercise required to elicit analgesic effects remains unknown. The purpose of this study was to compare neuropathic pain intensity, pain catastrophizing, use of coping strategies, and positive affect and well-being among Paralympic versus recreational athletes with SCI who experience chronic neuropathic pain. Forty-seven athletes with SCI (25 Paralympic, 27 recreational) completed the International SCI Pain Basic Data Set, Douleur Neuropathique-4, coping strategies questionnaire, pain catastrophizing scale, and SCI-quality of life assessment. RESULTS: Paralympic athletes reported significantly greater neuropathic pain (p = 0.032) and positive affect and well-being (p = 0.047) than recreational athletes. No other comparisons were significant (ps > 0.09). Significant, medium-sized positive correlations were observed between neuropathic pain and total minutes of moderate-intensity exercise (r = 0.335, p = 0.023) and average minutes per day of moderate-intensity exercise (r = 0.375, p = 0.010) over the past week. CONCLUSIONS: The results suggest that frequent moderate- to high-intensity exercise may exacerbate neuropathic pain sensations for persons with SCI. Research should investigate psychosocial and physiological mechanisms by which exercise may influence neuropathic pain to explain how Paralympic athletes with SCI are able to continue exercising while maintaining positive affect despite neuropathic pain.

Central neuropathic pain.

Central neuropathic pain arises from a lesion or disease of the central somatosensory nervous system such as brain injury, spinal cord injury, stroke, multiple sclerosis or related neuroinflammatory conditions. The incidence of central neuropathic pain differs based on its underlying cause. Individuals with spinal cord injury are at the highest risk; however, central post-stroke pain is the most prevalent form of central neuropathic pain worldwide. The mechanisms that underlie central neuropathic pain are not fully understood, but the pathophysiology likely involves intricate interactions and maladaptive plasticity within spinal circuits and brain circuits associated with nociception and antinociception coupled with neuronal hyperexcitability. Modulation of neuronal activity, neuron-glia and neuro-immune interactions and targeting pain-related alterations in brain connectivity, represent potential therapeutic approaches. Current evidence-based pharmacological treatments include antidepressants and gabapentinoids as first-line options. Non-pharmacological pain management options include self-management strategies, exercise and neuromodulation. A comprehensive pain history and clinical examination form the foundation of central neuropathic pain classification, identification of potential risk factors and stratification of patients for clinical trials. Advanced neurophysiological and neuroimaging techniques hold promise to improve the understanding of mechanisms that underlie central neuropathic pain and as predictive biomarkers of treatment outcome.

Perspectives on Data Sharing in Persons With Spinal Cord Injury.

Open data sharing of clinical research aims to improve transparency and support novel scientific discoveries. There are also risks, including participant identification and the potential for stigmatization. The perspectives of persons participating in research are needed to inform open data-sharing policies. The aim of the current study was to determine perspectives on data sharing in persons with spinal cord injury (SCI), including risks and benefits, and types of data people are most willing to share. A secondary aim was to examine predictors of willingness to share data. Persons with SCIs in the United States and Canada completed a survey developed and disseminated through various channels, including our community partner, the North American Spinal Cord Injury Consortium. The study collected data from 232 participants, with 52.2% from Canada and 42.2% from the United States, and the majority completed the survey in English. Most participants had previously participated in research and had been living with an SCI for ≥5 years. Overall, most participants reported that the potential benefits of data sharing outweighed the negatives, with persons with SCI seen as the most trustworthy partners for data sharing. The highest levels of concern were that information could be stolen and companies might use the information for marketing purposes. Persons with SCI were generally supportive of data sharing for research purposes. Clinical trials should consider including a statement on open data sharing in informed consents to better acknowledge the contribution of research participants in future studies.

Physical pain among Indigenous Peoples in Canada: a scoping review.

PURPOSE: Pain is a multifaceted experience shaped by various factors including context of pain, previous life events, and ongoing ethnocultural circumstances. Moreover, the definition of pain is inconsistent across cultures. Western medicine views physical pain (e.g., associated with a bone fracture) and nonphysical mental pain (e.g., depression) as two distinct conditions. Indigenous perspectives are often more wholistic, encompassing mental, spiritual, emotional, and physical hurt. The subjective nature of pain invites ample opportunity for discrimination in both its assessment and management. As such, it is important to consider Indigenous perspectives of pain in research and clinical practice. To investigate which aspects of Indigenous pain knowledge are currently considered by Western research, we conducted a scoping review of the literature on pain in Indigenous Peoples of Canada. SOURCE: In June 2021, we searched nine databases and downloaded 8,220 papers after removal of duplicates. Two independent reviewers screened abstracts and full-text articles. PRINCIPLE FINDINGS: Seventy-seven papers were included in the analysis. Using grounded theory, five themes emerged: pain measures/scales (n = 7), interventions (n = 13), pharmaceuticals (n = 17), pain expression/experiences (n = 45), and pain conditions (n = 70). CONCLUSION: This scoping review shows that there is a paucity of research on pain measurement in Indigenous Peoples of Canada. This finding is concerning in light of numerous studies reporting that Indigenous Peoples experience their pain as ignored, minimized, or disbelieved. Furthermore, a clear disconnect emerged between pain expression in Indigenous Peoples and assessment in medical professionals. We hope that this scoping review will serve to translate current knowledge to other non-Indigenous academics and to initiate meaningful collaboration with Indigenous partners. Future research led by Indigenous academics and community partners is critically needed to better address pain needs in Canada.

RéSUMé: OBJECTIF: La douleur est une expérience multidimensionnelle façonnée par divers facteurs, notamment le contexte de la douleur, les événements antérieurs de la vie et les circonstances ethnoculturelles courantes. De plus, la définition de la douleur change d'une culture à l'autre. La médecine occidentale considère la douleur physique (par exemple, celle associée à une fracture osseuse) et la douleur mentale non physique (par exemple, la dépression) comme deux conditions distinctes. Les perspectives autochtones sont souvent plus holistiques, englobant les blessures mentales, spirituelles, émotionnelles et physiques. La nature subjective de la douleur ouvre la voie à de nombreuses possibilités de discrimination tant dans son évaluation que dans sa prise en charge. C'est pourquoi il est important de tenir compte des perspectives autochtones en matière de douleur dans la recherche et la pratique clinique. Afin d'étudier quels aspects des connaissances autochtones concernant la douleur sont actuellement pris en compte par la recherche occidentale, nous avons réalisé une étude de portée de la littérature sur la douleur chez les peuples autochtones du Canada. SOURCES: En juin 2021, nous avons consulté neuf bases de données et téléchargé 8220 articles après suppression des doublons. Deux personnes ont passé en revue et évalué de manière indépendante les résumés et textes intégraux. CONSTATATIONS PRINCIPALES: Soixante-dix-sept articles ont été inclus dans l'analyse. À l'aide de la théorie ancrée, cinq thèmes sont ressortis : les mesures/échelles de la douleur (n = 7), les interventions (n = 13), les produits pharmaceutiques (n = 17), l'expression/les expériences de la douleur (n = 45), et les conditions de douleur (n = 70). CONCLUSION: Cette étude de portée démontre le peu de recherches sur la mesure de la douleur chez les peuples autochtones du Canada. Cette conclusion est préoccupante à la lumière de nombreuses études indiquant que les peuples autochtones voient leur douleur ignorée, minimisée ou discréditée. De plus, un décalage évident est apparu entre l'expression de la douleur chez les peuples autochtones et l'évaluation par les professionnels de la santé. Nous espérons que cette étude de portée servira à transférer les connaissances actuelles à d'autres chercheurs et chercheuses non autochtones et à établir une collaboration significative avec des partenaires autochtones. Les recherches futures menées par des universitaires autochtones et des partenaires de la collectivité sont essentielles pour mieux répondre aux besoins en matière de douleur au Canada.

Race-based reporting and participation of Black individuals in registered pain clinical trials, United States, 2000 to 2019.

ABSTRACT: There are numerous, well-established racial disparities in the management of pain. The degree to which these are evident at the stage of conducting clinical trials is unknown. To address this knowledge gap, we examined race-based reporting, participation of Black individuals, and the factors associated with reporting and participation in pain clinical trials in the United States. Data were extracted from Clinicaltrials.gov and published articles. One thousand two hundred trials met our inclusion criteria; 482 (40.2%) reported participant race. More recent, publicly funded, and larger trials were more likely to report race. Of 82,468 participants included in pain clinical trials that reported race, 15,101 were Black individuals (18.3%). Participation of Black individuals was significantly associated with pain type (ß = +27% in cardiovascular disease pain compared with acute pain, P < 0.05), study population (ß = +33% and +7% in pain in minoritized populations and women, respectively, compared with general population, P < 0.05), pain intervention (ß = +7.5% for trials of opioid interventions compared with nonopioid interventions, P < 0.05), and a diverse team of investigators (ß = +8.0% for studies incorporating a visible non-White investigator compared with those that did not, P < 0.05). Our results indicate that representation of Black participants in pain clinical trials generally aligns with national demographics in the United States. Increased representation corresponds with health conditions more prevalent among Black individuals (eg, cardiovascular disease) and with a diverse study team composition. Despite these encouraging results, less than half of pain trials reported race, which introduces potential publication bias and limits external validity.

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study.

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the RXSCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ ).

Pain-related gamma band activity is dependent on the features of nociceptive stimuli: a comparison of laser and contact heat.

Painful contact heat and laser stimulation offer an avenue to characterize nociceptive pathways involved in acute pain processing, by way of evoked potentials. Direct comparisons of radiant laser and contact heat are limited, particularly in context of examining time-frequency responses to stimulation. This is important in light of recent evidence to suggest that gamma band oscillations (GBOs) represent a functionally heterogeneous measure of pain. The purpose of the current study was to investigate differences in GBOs generated in response to laser and contact heat stimulation of the nondominant forearm. Following intensity matching to pain ratings, evoked electroencephalography (EEG) responses to laser and contact heat stimulation were examined in the time-frequency domain in the same participants (19 healthy adults) across two sessions. At ∼200 ms, both contact heat and laser stimulation resulted in significant, group-level event-related synchronization (ERS) in the low gamma band (i.e., 30-60 Hz) in central electrode locations (Cc, Cz, Ci). Laser stimulation also generated ERS in the 60-100 Hz range (i.e., high gamma), at ∼200 ms, while contact heat led to a significant period of desynchronization in the high gamma range between 400 and 600 ms. Both contact heat and laser GBOs were stronger on the central electrodes contralateral to the stimulated forearm, indicative of primary somatosensory cortex involvement. Based on our findings, and taken in conjunction with previous studies, laser and contact heat stimulation generate characteristically different responses in the brain, with only the former leading to high-frequency GBOs characteristic of painful stimuli.NEW & NOTEWORTHY Despite matching pain perception between noxious laser and contact heat stimuli, we report notable differences in gamma band oscillations (GBO), measured via electroencephalography. GBOs produced following contact heat more closely resembled that of nonnoxious stimuli, while GBOs following laser stimuli were in line with previous reports. Taken together, laser and contact heat stimulation generate characteristically different responses in the brain, with only the former leading to high-frequency GBOs characteristic of painful stimuli.

Supraspinal facilitation to repetitive painful stimulation: a laser-evoked potential study.

To better characterize central modulation mechanisms involved in the processing of daily repetitive painful stimulation, laser-evoked potentials (LEPs) were recorded at and away from the conditioning area in healthy participants. In addition, we aimed to evaluate a repetitive painful stimulation paradigm that could be conducted in a shorter time frame than previous studies. Collectively, continuous pain rating, warm and heat pain threshold results suggest that sensitivity to pain was reduced 24 h after the shortened repeated painful stimulation. Laser-evoked potentials revealed a significant increase in the contralateral arm to where the conditioning stimulus was applied. This finding was specific to noxious conditioning (i.e., not seen in the control brush experiment). These results provide neurophysiological evidence of pain facilitation resulting from prolonged exposure to painful heat, potentially arising in supraspinal structures.NEW & NOTEWORTHY We provide evidence for supraspinal faciliation measured via laser-evoked potentails in response to a shortened and methodologically improved repetitive painful stimulation paradigm, serving the broader scientific community, insofar as providing a paradigm can feasibly be completed in a caldendar week. These findings provide new evidence using laser-evoked potentials indicating increased activation of the anterior cingulate cortex during prolonged pain processing.

Systemic Immune Profile Predicts the Development of Infections in Patients with Spinal Cord Injuries.

Patients with spinal cord injury (SCI) frequently develop infections that may affect quality of life, be life-threatening, and impair their neurological recovery in the acute and subacute injury phases. Therefore, identifying patients with SCI at risk for developing infections in this stage is of utmost importance. We determined the systemic levels of immune cell populations, cytokines, chemokines, and growth factors in 81 patients with traumatic SCI at 4 weeks after injury and compared them with those of 26 age-matched healthy control subjects. Patients who developed infections between 4 and 16 weeks after injury exhibited higher numbers of neutrophils and eosinophils, as well as lower numbers of lymphocytes and eotaxin-1 (CCL11) levels. Accordingly, lasso logistic regression showed that incomplete lesions (American Spinal Injury Association Impairment Scale [AIS] C and D grades), the levels of eotaxin-1, and the number of lymphocytes, basophils, and monocytes are predictive of lower odds for infections. On the other hand, the number of neutrophils and eosinophils as well as, in a lesser extent, the levels of IP-10 (CXCL10), MCP-1 (CCL2), BDNF [brain-derived neurotrophic factor], and vascular endothelial growth factor [VEGF]-A, are predictors of increased susceptibility for developing infections. Overall, our results point to systemic immune disbalance after SCI as predictors of infection in a period when infections may greatly interfere with neurological and functional recovery and suggest new pathways and players to further explore novel therapeutic strategies.

Quality of meta-analyses of non-opioid, pharmacological, perioperative interventions for chronic postsurgical pain: a systematic review.

BACKGROUND: In an attempt to aggregate observations from clinical trials, several meta-analyses have been published examining the effectiveness of systemic, non-opioid, pharmacological interventions to reduce the incidence of chronic postsurgical pain. OBJECTIVE: To inform the design and reporting of future studies, the purpose of our study was to examine the quality of these meta-analyses. EVIDENCE REVIEW: We conducted an electronic literature search in Embase, MEDLINE, and the Cochrane Database of Systematic Reviews. Published meta-analyses, from the years 2010 to 2020, examining the effect of perioperative, systemic, non-opioid pharmacological treatments on the incidence of chronic postsurgical pain in adult patients were identified. Data extraction focused on methodological details. Meta-analysis quality was assessed using the A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) critical appraisal tool. FINDINGS: Our search yielded 17 published studies conducting 58 meta-analyses for gabapentinoids (gabapentin and pregabalin), ketamine, lidocaine, non-steroidal anti-inflammatory drugs, and mexiletine. According to AMSTAR 2, 88.2% of studies (or 15/17) were low or critically low in quality. The most common critical element missing was an analysis of publication bias. Trends indicated an improvement in quality over time and association with journal impact factor. CONCLUSIONS: With few individual trials adequately powered to detect treatment effects, meta-analyses play a crucial role in informing the perioperative management of chronic postsurgical pain. In light of this inherent value and despite a number of attempts, high-quality meta-analyses are still needed. PROSPERO REGISTRATION NUMBER: CRD42021230941.

Efficacy of topical cannabinoids in the management of pain: a systematic review and meta-analysis of animal studies.

BACKGROUND/IMPORTANCE: Cannabinoids are emerging as an alternative pain management option, preliminarily supported by preclinical and clinical studies. Unwanted side effects from oral or inhaled cannabinoids remain, however, a major barrier to widespread use. Peripherally acting cannabinoids (eg, topically applied) may circumvent these side effects while providing localized pain management. OBJECTIVE: Our purpose was to systematically review the literature on the effectiveness of peripherally acting cannabinoids for pain management. EVIDENCE REVIEW: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, and PubMed databases. Included studies examined the effect of topical/peripherally administered cannabinoids on pain ratings in humans, as well as pain-related outcomes in animals (eg, paw withdrawal). Due to a lack of trials, human studies were summarized in a narrative synthesis. Separate meta-analyses were performed for animal studies using radiant tail flick or paw withdrawal outcomes. FINDINGS: Our search yielded 1182 studies following removal of duplicates, with 46 studies (6 human, 40 animal) included. Human studies (one randomized controlled trial and five case studies/series) reported no adverse events to topical cannabinoids and preliminary evidence of decreased pain ratings. Animal studies reporting tail flick (5) (2.81, 95% CI 1.93 to 3.69, p<0.001) and mechanical withdrawal (11) (2.74, 95% CI 1.82 to 3.67, p<0.001) reported prolonged responses (analgesia) in peripheral cannabinoid groups compared with controls. CONCLUSIONS: Preclinical animal studies provided low-quality evidence for peripherally administered cannabinoids to provide regional, antinociceptive effects. The scarcity of high-quality human studies underscores the need to translate preclinical evidence into well-controlled human trials.

Characterization of Hyperacute Neuropathic Pain after Spinal Cord Injury: A Prospective Study.

There is currently a lack of information regarding neuropathic pain in the very early stages of spinal cord injury (SCI). In the present study, neuropathic pain was assessed using the Douleur Neuropathique 4 Questions (DN4) for the patient's worst pain within the first 5 days of injury (i.e., hyperacute) and on follow-up at 3, 6, and 12 months. Within the hyperacute time frame (i.e., 5 days), at- and below-level neuropathic pain were reported as the worst pain in 23% (n = 18) and 5% (n = 4) of individuals with SCI, respectively. Compared to the neuropathic pain observed in this hyperacute setting, late presenting neuropathic pain was characterized by more intense painful electrical and cold sensations, but less itching sensations. Phenotypic differences between acute and late neuropathic pain support the incorporation of timing into a mechanism-based classification of neuropathic pain after SCI. The diagnosis of acute neuropathic pain after SCI is challenged by the presence of nociceptive and neuropathic pains, with the former potentially masking the latter. This may lead to an underestimation of the incidence of neuropathic pain during the very early, hyperacute time points post-injury. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01279811) PERSPECTIVE: This article presents distinct pain phenotypes of hyperacute and late presenting neuropathic pain after spinal cord injury and highlights the challenges of pain assessments in the acute phase after injury. This information may be relevant to clinical trial design and broaden our understanding of neuropathic pain mechanisms after spinal cord injury.

A data-driven T2 relaxation analysis approach for myelin water imaging: Spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS).

PURPOSE: The decomposition of multi-exponential decay data into a T2 spectrum poses substantial challenges for conventional fitting algorithms, including non-negative least squares (NNLS). Based on a combination of the resolution limit constraint and machine learning neural network algorithm, a data-driven and highly tailorable analysis method named spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS) was proposed. THEORY AND METHODS: The theory of SAME-ECOS was derived. Then, a paradigm was presented to demonstrate the SAME-ECOS workflow, consisting of a series of calculation, simulation, and model training operations. The performance of the trained SAME-ECOS model was evaluated using simulations and six in vivo brain datasets. The code is available at https://github.com/hanwencat/SAME-ECOS. RESULTS: Using NNLS as the baseline, SAME-ECOS achieved over 15% higher overall cosine similarity scores in producing the T2 spectrum, and more than 10% lower mean absolute error in calculating the myelin water fraction (MWF), as well as demonstrated better robustness to noise in the simulation tests. Applying to in vivo data, MWF from SAME-ECOS and NNLS was highly correlated among all study participants. However, a distinct separation of the myelin water peak and the intra/extra-cellular water peak was only observed in the mean T2 spectra determined using SAME-ECOS. In terms of data processing speed, SAME-ECOS is approximately 30 times faster than NNLS, achieving a whole-brain analysis in 3 min. CONCLUSION: Compared with NNLS, the SAME-ECOS method yields much more reliable T2 spectra in a dramatically shorter time, increasing the feasibility of multi-component T2 decay analysis in clinical settings.

A New Score Based on the International Standards for Neurological Classification of Spinal Cord Injury for Integrative Evaluation of Changes in Sensorimotor Functions.

Sensorimotor function of patients with spinal cord injury (SCI) is commonly assessed according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). From the ISNCSCI segmental motor and sensory assessments, upper and lower extremity motor scores (UEMS and LEMS), sum scores of pinprick (PP) and light touch (LT) sensation, the neurological level of injury (NLI) and the classification of lesion severity according to the American Spinal Injury Association Impairment Scale (AIS) grade are derived. Changes of these parameters over time are used widely to evaluate neurological recovery. Evaluating recovery based on a single ISNCSCI scoring or classification variable, however, may misestimate overall recovery. Here, we propose an Integrated Neurological Change Score (INCS) based on the combination of normalized changes between two time points of UEMS, LEMS, and total PP and LT scores. To assess the agreement of INCS with clinical judgment of meaningfulness of neurological changes, changes of ISNCSCI variables between two time points of 88 patients from an independent cohort were rated by 20 clinical experts according to a five-categories Likert Scale. As for individual ISNCSCI variables, neurological change measured by INCS is associated with severity (AIS grade), age, and time since injury, but INCS better reflects clinical judgment about meaningfulness of neurological changes than individual ISNCSCI variables. In addition, INCS is related to changes in functional independence measured by the Spinal Cord Independence Measure (SCIM) in patients with tetraplegia. The INCS may be a useful measure of overall neurological change in clinical studies.

Can Magnetic Resonance Imaging Reveal Lower Motor Neuron Damage after Traumatic Spinal Cord Injury? A Scoping Review.

Restoring muscle function to patients with spinal cord injuries (SCIs) will invariably require a functioning lower motor neuron (LMN). As techniques such as nerve transfer surgery emerge, characterizing the extent of LMN damage associated with SCIs becomes clinically important. Current methods of LMN diagnosis have inherent limitations that could potentially be overcome by the development of magnetic resonance imaging (MRI) biomarkers: specific features on MRI that are indicative of LMN integrity. To identify research on MRI biomarkers of LMN damage in the acute phase after SCI, we searched PubMed, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials for articles published from inception to April 27, 2021. Overall, 2 of 58 unique articles screened met our inclusion criteria, both of which were small studies. We therefore identify MRI biomarkers of LMN damage overlying SCI as a notable gap in the literature. Because of the lack of existing literature on this specific problem, we further our discussion by examining concepts explored in research characterizing MRI biomarkers of spinal cord and neuronal damage in different contexts that may provide value in future work to identify a biomarker for LMN damage in SCI. We conclude that MRI biomarkers of LMN damage in SCI is an underexplored, but promising, area of research as emerging, function-restoring therapies requiring this information continue to advance.

Clinical trials and tribulations: lessons from spinal cord injury studies registered on ClinicalTrials.gov.

STUDY DESIGN: Article. OBJECTIVE: ClinicalTrials.gov is an online trial registry that provides public access to information on past, present, and future clinical trials. While increasing transparency in research, the quality of the information provided in trial registrations is highly variable. The objective of this study is to assess key areas of information on ClinicalTrials.gov in interventional trials involving people with spinal cord injuries. SETTING: Interventional trials on ClinicalTrials.gov involving people with spinal cord injuries. METHODS: A subset of data on interventional spinal cord injury trials was downloaded from ClinicalTrials.gov. Reviewers extracted information pertaining to study type, injury etiology, spinal cord injury characteristics, timing, study status, and results. RESULTS: Of the interventional trial registrations reviewed, 62.5%, 58.6%, and 24.3% reported injury level, severity, and etiology, respectively. The timing of intervention relative to injury was reported in 72.8% of registrations. Most trials identified a valid study status (89.2%), but only 23.5% of those completed studies had posted results. CONCLUSIONS: Our review provides a snapshot of interventional clinical trials conducted in the field of spinal cord injury and registered in ClinicalTrials.gov. Areas for improvement were identified with regards to reporting injury characteristics, as well as posting results.

Eccentric rehabilitation induces white matter plasticity and sensorimotor recovery in chronic spinal cord injury.

Experience-dependent white matter plasticity offers new potential for rehabilitation-induced recovery after neurotrauma. This first-in-human translational experiment combined myelin water imaging in humans and genetic fate-mapping of oligodendrocyte lineage cells in mice to investigate whether downhill locomotor rehabilitation that emphasizes eccentric muscle actions promotes white matter plasticity and recovery in chronic, incomplete spinal cord injury (SCI). In humans, of 20 individuals with SCI that enrolled, four passed the imaging screen and had myelin water imaging before and after a 12-week (3 times/week) downhill locomotor treadmill training program (SCI + DH). One individual was excluded for imaging artifacts. Uninjured control participants (n = 7) had two myelin water imaging sessions within the same day. Changes in myelin water fraction (MWF), a histopathologically-validated myelin biomarker, were analyzed in a priori motor learning and non-motor learning brain regions and the cervical spinal cord using statistical approaches appropriate for small sample sizes. PDGFRα-CreERT2:mT/mG mice, that express green fluorescent protein on oligodendrocyte precursor cells and subsequent newly-differentiated oligodendrocytes upon tamoxifen-induced recombination, were either naive (n = 6) or received a moderate (75 kilodyne), contusive SCI at T9 and were randomized to downhill training (n = 6) or unexercised groups (n = 6). We initiated recombination 29 days post-injury, seven days prior to downhill training. Mice underwent two weeks of daily downhill training on the same 10% decline grade used in humans. Between-group comparison of functional (motor and sensory) and histological (oligodendrogenesis, oligodendroglial/axon interaction, paranodal structure) outcomes occurred post-training. In humans with SCI, downhill training increased MWF in brain motor learning regions (postcentral, precuneus) and mixed motor and sensory tracts of the ventral cervical spinal cord compared to control participants (P < 0.05). In mice with thoracic SCI, downhill training induced oligodendrogenesis in cervical dorsal and lateral white matter, increased axon-oligodendroglial interactions, and normalized paranodal structure in dorsal column sensory tracts (P < 0.05). Downhill training improved sensorimotor recovery in mice by normalizing hip and knee motor control and reducing hyperalgesia, both of which were associated with new oligodendrocytes in the cervical dorsal columns (P < 0.05). Our findings indicate that eccentric-focused, downhill rehabilitation promotes white matter plasticity and improved function in chronic SCI, likely via oligodendrogenesis in nervous system regions activated by the training paradigm. Together, these data reveal an exciting role for eccentric training in white matter plasticity and sensorimotor recovery after SCI.

Natural Progression of Routine Laboratory Markers after Spinal Trauma: A Longitudinal, Multi-Cohort Study.

Our objective was to track and quantify the natural course of serological markers over the 1st year following spinal cord injury. For that purpose, data on serological markers, demographics, and injury characteristics were extracted from medical records of a clinical trial (Sygen) and an ongoing observational cohort study (Murnau study). The primary outcomes were concentration/levels/amount of commonly collected serological markers at multiple time points. Two-way analysis of variance (ANOVA) and mixed-effects regression techniques were used to account for the longitudinal data and adjust for potential confounders. Trajectories of serological markers contained in both data sources were compared using the slope of progression. Our results show that, at baseline (≤ 2 weeks post-injury), most serological markers were at pathological levels, but returned to normal values over the course of 6-12 months post-injury. The baseline levels and longitudinal trajectories were dependent on injury severity. More complete injuries were associated with more pathological values (e.g., hematocrit, ANOVA test; χ2 = 68.93, df = 3, adjusted p value <0.001, and χ2 = 73.80, df = 3, adjusted p value <0.001, in the Sygen and Murnau studies, respectively). Comparing the two databases revealed some differences in the serological markers, which are likely attributable to differences in study design, sample size, and standard of care. We conclude that because of trauma-induced physiological perturbations, serological markers undergo marked changes over the course of recovery, from initial pathological levels that normalize within a year. The findings from this study are important, as they provide a benchmark for clinical decision making and prospective clinical trials. All results can be interactively explored on the Haemosurveillance web site (https://jutzelec.shinyapps.io/Haemosurveillance/) and GitHub repository (https://github.com/jutzca/Systemic-effects-of-Spinal-Cord-Injury).

A Systematic Review of Safety Reporting in Acute Spinal Cord Injury Clinical Trials: Challenges and Recommendations.

Accurate safety information in published clinical trials guides the assessment of risk-benefit, as well as the design of future clinical trials. Comprehensive reporting of adverse events, toxicity, and discontinuations from acute spinal cord injury clinical trials is an essential step in this process. Here, we sought to assess the degree of "satisfactoriness" of reporting in past clinical trials in spinal cord injury. A review of citations from MEDLINE and EMBASE identified eligible clinical trials in acute (within 30 days) spinal cord injury. English language studies, published between 1980 and 2020, with sensory, motor, or autonomic neurological assessments as the primary outcome measure were eligible for inclusion. Criteria were then established to qualify the safety reporting as satisfactory (i.e., distinguished severe/life-threatening events), partially satisfactory, or unsatisfactory (i.e., only mentioned in general statements, or reported but without distinguishing severe events). A total of 40 trials were included. Satisfactory reporting for clinical adverse events was observed in 30% of trials; partially satisfactory was achieved by 10% of the trials, and the remaining 60% were unsatisfactory. The majority of trials were determined to be unsatisfactory for the reporting of laboratory-defined toxicity (82.5%); only 17.5% were satisfactory. Discontinuations were satisfactorily reported for the majority of trials (80%), with the remaining partially satisfactory (5%) or unsatisfactory (15%). Reporting of safety in clinical trials for acute spinal cord injury is suboptimal. Due to the complexities of acute spinal cord injury (e.g., polytrauma, multiple systems affected), tailored and specific standards for tracking adverse events and safety reporting should be established.