Contact-Heat Evoked Potentials: Insights into Pain Processing in CRPS Type I.

Purpose: The pathophysiological mechanisms underlying the development of chronic pain in complex regional pain syndrome (CRPS) are diverse and involve both peripheral and central changes in pain processing, such as sensitization of the nociceptive system. The aim of this study was to objectively distinguish the specific changes occurring at both peripheral and central levels in nociceptive processing in individuals with chronic CRPS type I. Patients and Methods: Nineteen individuals with chronic CRPS type I and 16 age- and sex-matched healthy controls (HC) were recruited. All individuals underwent a clinical examination and pain assessment in the most painful limb, the contralateral limb, and a pain-free control area to distinguish between peripheral and central mechanisms. Contact-heat evoked potentials (CHEPs) were recorded after heat stimulation of the three different areas and amplitudes and latencies were analyzed. Additionally, quantitative sensory testing (QST) was performed in all three areas. Results: Compared to HC, CHEP amplitudes in CRPS were only increased after stimulation of the painful area (p=0.025), while no increases were observed for the pain-free control area (p=0.14). None of the CHEP latencies were different between the two cohorts (all p>0.23). Furthermore, individuals with CRPS showed higher pain ratings after stimulation of the painful limb compared to their contralateral limb (p=0.013). Lastly, compared to HC, mechanical (p=0.012) and thermal (p=0.046) sensitivity was higher in the painful area of the CRPS cohort. Conclusion: This study provides neurophysiological evidence supporting an intact thermo-nociceptive pathway with signs of peripheral sensitization, such as hyperexcitable primary afferent nociceptors, in individuals with CRPS type I. This is further supported by the observation of mechanical and thermal gain of sensation only in the painful limb. Additionally, the increased CHEP amplitudes might be related to fear-induced alterations of nociceptive processing.

COVID-19 and spinal cord injury: clinical presentation, clinical course, and clinical outcomes of people hospitalised.

STUDY DESIGN: Retrospective study OBJECTIVES: To describe the presenting symptoms/signs, clinical course and outcomes in hospitalised people with spinal cord injury (SCI) and symptomatic COVID-19 infections. SETTING: One university hospital and two SCI centres in Switzerland. METHODS: Descriptive analysis of symptoms/signs, clinical course and outcomes of people with SCI with symptomatic COVID-19 infections and need for hospitalisation. RESULTS: Twenty-two people with SCI were included, 15 (68%) were male, median age 64.5 years (interquartile range, IQR, 52-73 years). Nine (41%) had tetraplegia, and eight (36%) were classified with motor-complete lesions. Frequent clinical symptoms were fever (59%), coughing (54%), fatigue (50%), and dyspnoea (27%). Most frequent complications were bacterial pulmonary superinfection (18%), and acute respiratory distress syndrome (18%). Fifteen persons (68%) needed oxygen therapy during the course of hospitalisation, and 7 (32%) people were ventilated. Median length of stay (LOS) was 23 days (IQR 15-35), varying by age for people under 60 years with a median LOS of 9 days (IQR 8-27), and for those older than 60 years with a median of 34 days (IQR 17-39), respectively. In total, 3 persons (14%) died during hospitalisation, all older with paraplegia. CONCLUSIONS: Typical symptoms like fever and coughing were not present in all people. People with tetraplegia did not demonstrate worse outcomes, on the contrary, they had shorter LOS, no difference in ventilation needs, and no higher mortality compared to people with paraplegia. Older people showed longer LOS. This study recommends close supervision of the SCI population to detect early signs and symptoms of COVID-19 infection.

Reliability of patient-specific gait profiles with inertial measurement units during the 2-min walk test in incomplete spinal cord injury.

Most established clinical walking tests assess specific aspects of movement function (velocity, endurance, etc.) but are generally unable to determine specific biomechanical or neurological deficits that limit an individual's ability to walk. Recently, inertial measurement units (IMU) have been used to collect objective kinematic data for gait analysis and could be a valuable extension for clinical assessments (e.g., functional walking measures). This study assesses the reliability of an IMU-based overground gait analysis during the 2-min walk test (2mWT) in individuals with spinal cord injury (SCI). Furthermore, the study elaborates on the capability of IMUs to distinguish between different gait characteristics in individuals with SCI. Twenty-six individuals (aged 22-79) with acute or chronic SCI (AIS: C and D) completed the 2mWT with IMUs attached above each ankle on 2 test days, separated by 1 to 7 days. The IMU-based gait analysis showed good to excellent test-retest reliability (ICC: 0.77-0.99) for all gait parameters. Gait profiles remained stable between two measurements. Sensor-based gait profiling was able to reveal patient-specific gait impairments even in individuals with the same walking performance in the 2mWT. IMUs are a valuable add-on to clinical gait assessments and deliver reliable information on detailed gait pathologies in individuals with SCI.Trial registration: NCT04555759.

Longitudinal motor system changes from acute to chronic spinal cord injury.

BACKGROUND AND PURPOSE: In acute spinal cord injury (SCI), magnetic resonance imaging (MRI) reveals tissue bridges and neurodegeneration for 2 years. This 5-year study aims to track initial lesion changes, subsequent neurodegeneration, and their impact on recovery. METHODS: This prospective longitudinal study enrolled acute SCI patients and healthy controls who were assessed clinically-and by MRI-regularly from 3 days postinjury up to 60 months. We employed histologically cross-validated quantitative MRI sequences sensitive to volume, myelin, and iron changes, thereby reflecting indirectly processes of neurodegeneration and neuroinflammation. General linear models tracked lesion and remote changes in volume, myelin- and iron-sensitive magnetic resonance indices over 5 years. Associations between lesion, degeneration, and recovery (using the Spinal Cord Independence Measure [SCIM] questionnaire and the International Standards for Neurological Classification of Spinal Cord Injury total motor score) were assessed. RESULTS: Patients' motor scores improved by an average of 12.86 (95% confidence interval [CI] = 6.70-19.00) points, and SCIM by 26.08 (95% CI = 17.00-35.20) points. Within 3-28 days post-SCI, lesion size decreased by more than two-thirds (3 days: 302.52 ± 185.80 mm2 , 28 days: 76.77 ± 88.62 mm2 ), revealing tissue bridges. Cervical cord and corticospinal tract volumes transiently increased in SCI patients by 5% and 3%, respectively, accompanied by cervical myelin decreases and iron increases. Over time, progressive atrophy was observed in both regions, which was linked to early lesion dynamics. Tissue bridges, reduced swelling, and myelin content decreases were predictive of long-term motor score recovery and improved SCIM score. CONCLUSIONS: Studying acute changes and their impact on longer follow-up provides insights into SCI trajectory, highlighting the importance of acute intervention while indicating the potential to influence outcomes in the later stages.

Studying missingness in spinal cord injury data: challenges and impact of data imputation.

BACKGROUND: In the last decades, medical research fields studying rare conditions such as spinal cord injury (SCI) have made extensive efforts to collect large-scale data. However, most analysis methods rely on complete data. This is particularly troublesome when studying clinical data as they are prone to missingness. Often, researchers mitigate this problem by removing patients with missing data from the analyses. Less commonly, imputation methods to infer likely values are applied. OBJECTIVE: Our objective was to study how handling missing data influences the results reported, taking the example of SCI registries. We aimed to raise awareness on the effects of missing data and provide guidelines to be applied for future research projects, in SCI research and beyond. METHODS: Using the Sygen clinical trial data (n = 797), we analyzed the impact of the type of variable in which data is missing, the pattern according to which data is missing, and the imputation strategy (e.g. mean imputation, last observation carried forward, multiple imputation). RESULTS: Our simulations show that mean imputation may lead to results strongly deviating from the underlying expected results. For repeated measures missing at late stages (> = 6 months after injury in this simulation study), carrying the last observation forward seems the preferable option for the imputation. This simulation study could show that a one-size-fit-all imputation strategy falls short in SCI data sets. CONCLUSIONS: Data-tailored imputation strategies are required (e.g., characterisation of the missingness pattern, last observation carried forward for repeated measures evolving to a plateau over time). Therefore, systematically reporting the extent, kind and decisions made regarding missing data will be essential to improve the interpretation, transparency, and reproducibility of the research presented.

Mixed methods usability evaluation of an assistive wearable robotic hand orthosis for people with spinal cord injury.

BACKGROUND: Robotic hand orthoses (RHO) aim to provide grasp assistance for people with sensorimotor hand impairment during daily tasks. Many of such devices have been shown to bring a functional benefit to the user. However, assessing functional benefit is not sufficient to evaluate the usability of such technologies for daily life application. A comprehensive and structured evaluation of device usability not only focusing on effectiveness but also efficiency and satisfaction is required, yet often falls short in existing literature. Mixed methods evaluations, i.e., assessing a combination of quantitative and qualitative measures, allow to obtain a more holistic picture of all relevant aspects of device usability. Considering these aspects already in early development stages allows to identify design issues and generate generalizable benchmarks for future developments. METHODS: We evaluated the short-term usability of the RELab tenoexo, a RHO for hand function assistance, in 15 users with tetraplegia after a spinal cord injury through a comprehensive mixed methods approach. We collected quantitative data using the Action Research Arm Test (ARAT), the System Usability Scale (SUS), and timed tasks such as the donning process. In addition, qualitative data were collected through semi-structured interviews and user observations, and analyzed with a thematic analysis to enhance the usability evaluation. All insights were attributed and discussed in relation to specifically defined usability attributes such as comfort, ease of use, functional benefit, and safety. RESULTS: The RELab tenoexo provided an immediate functional benefit to the users, resulting in a mean improvement of the ARAT score by 5.8 points and peaking at 15 points improvement for one user (clinically important difference: 5.7 points). The mean SUS rating of 60.6 represents an adequate usability, however, indicating that especially the RHO donning (average task time = 295 s) was perceived as too long and cumbersome. The participants were generally very satisfied with the ergonomics (size, dimensions, fit) of the RHO. Enhancing the ease of use, specifically in donning, increasing the provided grasping force, as well as the availability of tailoring options and customization were identified as main improvement areas to promote RHO usability. CONCLUSION: The short-term usability of the RELab tenoexo was thoroughly evaluated with a mixed methods approach, which generated valuable data to improve the RHO in future iterations. In addition, learnings that might be transferable to the evaluation and design of other RHO were generated, which have the potential to increase the daily life applicability and acceptance of similar technologies.

Investigation of perfusion impairment in degenerative cervical myelopathy beyond the site of cord compression.

The aim of this study was to determine tissue-specific blood perfusion impairment of the cervical cord above the compression site in patients with degenerative cervical myelopathy (DCM) using intravoxel incoherent motion (IVIM) imaging. A quantitative MRI protocol, including structural and IVIM imaging, was conducted in healthy controls and patients. In patients, T2-weighted scans were acquired to quantify intramedullary signal changes, the maximal canal compromise, and the maximal cord compression. T2*-weighted MRI and IVIM were applied in all participants in the cervical cord (covering C1-C3 levels) to determine white matter (WM) and grey matter (GM) cross-sectional areas (as a marker of atrophy), and tissue-specific perfusion indices, respectively. IVIM imaging resulted in microvascular volume fraction ([Formula: see text]), blood velocity ([Formula: see text]), and blood flow ([Formula: see text]) indices. DCM patients additionally underwent a standard neurological clinical assessment. Regression analysis assessed associations between perfusion parameters, clinical outcome measures, and remote spinal cord atrophy. Twenty-nine DCM patients and 30 healthy controls were enrolled in the study. At the level of stenosis, 11 patients showed focal radiological evidence of cervical myelopathy. Above the stenosis level, cord atrophy was observed in the WM (- 9.3%; p = 0.005) and GM (- 6.3%; p = 0.008) in patients compared to healthy controls. Blood velocity (BV) and blood flow (BF) indices were decreased in the ventral horns of the GM (BV: - 20.1%, p = 0.0009; BF: - 28.2%, p = 0.0008), in the ventral funiculi (BV: - 18.2%, p = 0.01; BF: - 21.5%, p = 0.04) and lateral funiculi (BV: - 8.5%, p = 0.03; BF: - 16.5%, p = 0.03) of the WM, across C1-C3 levels. A decrease in microvascular volume fraction was associated with GM atrophy (R = 0.46, p = 0.02). This study demonstrates tissue-specific cervical perfusion impairment rostral to the compression site in DCM patients. IVIM indices are sensitive to remote perfusion changes in the cervical cord in DCM and may serve as neuroimaging biomarkers of hemodynamic impairment in future studies. The association between perfusion impairment and cervical cord atrophy indicates that changes in hemodynamics caused by compression may contribute to the neurodegenerative processes in DCM.

Sensory phenotypes in complex regional pain syndrome and chronic low back pain-indication of common underlying pathomechanisms.

Introduction: First-line pain treatment is unsatisfactory in more than 50% of chronic pain patients, likely because of the heterogeneity of mechanisms underlying pain chronification. Objectives: This cross-sectional study aimed to better understand pathomechanisms across different chronic pain cohorts, regardless of their diagnoses, by identifying distinct sensory phenotypes through a cluster analysis. Methods: We recruited 81 chronic pain patients and 63 age-matched and sex-matched healthy controls (HC). Two distinct chronic pain cohorts were recruited, ie, complex regional pain syndrome (N = 20) and low back pain (N = 61). Quantitative sensory testing (QST) was performed in the most painful body area to investigate somatosensory changes related to clinical pain. Furthermore, QST was conducted in a pain-free area to identify remote sensory alterations, indicating more widespread changes in somatosensory processing. Results: Two clusters were identified based on the QST measures in the painful area, which did not represent the 2 distinct pain diagnoses but contained patients from both cohorts. Cluster 1 showed increased pain sensitivities in the painful and control area, indicating central sensitization as a potential pathomechanism. Cluster 2 showed a similar sensory profile as HC in both tested areas. Hence, either QST was not sensitive enough and more objective measures are needed to detect sensitization within the nociceptive neuraxis or cluster 2 may not have pain primarily because of sensitization, but other factors such as psychosocial ones are involved. Conclusion: These findings support the notion of shared pathomechanisms irrespective of the pain diagnosis. Conversely, different mechanisms might contribute to the pain of patients with the same diagnosis.

Nerve Transfer After Cervical Spinal Cord Injury: Who Has a "Time Sensitive" Injury Based on Electrodiagnostic Findings?

OBJECTIVE: To use the ulnar compound muscle action potential (CMAP) to abductor digiti minimi (ADM) to identify the proportion of individuals with cervical spinal cord injury (SCI) who have lower motor neuron (LMN) abnormalities involving the C8-T1 spinal nerve roots, within 3-6 months, and thus may influence the response to nerve transfer surgery. DESIGN: Retrospective analysis of prospectively collected data. Data were analyzed from European Multicenter Study About SCI database. SETTING: Multi-center, academic hospitals. PARTICIPANTS: We included 79 subjects (age=41.4±17.7, range:16-75; 59 men; N=79), who were classified as cervical level injuries 2 weeks after injury and who had manual muscle strength examinations that would warrant consideration for nerve transfer (C5≥4, C8<3). INTERVENTIONS: None. MAIN OUTCOME MEASURES: The ulnar nerve CMAP amplitude to ADM was used as a proxy measure for C8-T1 spinal segment health. CMAP amplitude was stratified into very abnormal (<1.0 mV), sub-normal (1.0-5.9 mV), and normal (>6.0 mV). Analysis took place at 3 (n=148 limbs) and 6 months (n=145 limbs). RESULTS: At 3- and 6-month post-injury, 33.1% and 28.3% of limbs had very abnormal CMAP amplitudes, respectively, while in 54.1% and 51.7%, CMAPs were sub-normal. Median change in amplitude from 3 to 6 months was 0.0 mV for very abnormal and 1.0 mV for subnormal groups. A 3-month ulnar CMAP <1 mV had a positive predictive value of 0.73 (95% CI 0.69-0.76) and 0.78 (95% CI 0.75-0.80) for C8 and T1 muscle strength of 0 vs 1 or 2. CONCLUSION: A high proportion of individuals have ulnar CMAPs below the lower limit of normal 3- and 6-month post cervical SCI and may also have intercurrent LMN injury. Failure to identify individuals with LMN denervation could result in a lost opportunity to improve hand function through timely nerve transfer surgeries.

Increased cranio-caudal spinal cord oscillations are the cardinal pathophysiological change in degenerative cervical myelopathy.

Introduction: Degenerative cervical myelopathy (DCM) is the most common cause of non-traumatic incomplete spinal cord injury, but its pathophysiology is poorly understood. As spinal cord compression observed in standard MRI often fails to explain a patient's status, new diagnostic techniques to assess DCM are one of the research priorities. Minor cardiac-related cranio-caudal oscillations of the cervical spinal cord are observed by phase-contrast MRI (PC-MRI) in healthy controls (HCs), while they become pathologically increased in patients suffering from degenerative cervical myelopathy. Whether transversal oscillations (i.e., anterior-posterior and right-left) also change in DCM patients is not known. Methods: We assessed spinal cord motion simultaneously in all three spatial directions (i.e., cranio-caudal, anterior-posterior, and right-left) using sagittal PC-MRI and compared physiological oscillations in 18 HCs to pathological changes in 72 DCM patients with spinal canal stenosis. The parameter of interest was the amplitude of the velocity signal (i.e., maximum positive to maximum negative peak) during the cardiac cycle. Results: Most patients suffered from mild DCM (mJOA score 16 (14-18) points), and the majority (68.1%) presented with multisegmental stenosis. The spinal canal was considerably constricted in DCM patients in all segments compared to HCs. Under physiological conditions in HCs, the cervical spinal cord oscillates in the cranio-caudal and anterior-posterior directions, while right-left motion was marginal [e.g., segment C5 amplitudes: cranio-caudal: 0.40 (0.27-0.48) cm/s; anterior-posterior: 0.18 (0.16-0.29) cm/s; right-left: 0.10 (0.08-0.13) cm/s]. Compared to HCs, DCM patients presented with considerably increased cranio-caudal oscillations due to the cardinal pathophysiologic change in non-stenotic [e.g., segment C5 amplitudes: 0.79 (0.49-1.32) cm/s] and stenotic segments [.g., segment C5 amplitudes: 0.99 (0.69-1.42) cm/s]). In contrast, right-left [e.g., segment C5 amplitudes: non-stenotic segment: 0.20 (0.13-0.32) cm/s; stenotic segment: 0.11 (0.09-0.18) cm/s] and anterior-posterior oscillations [e.g., segment C5 amplitudes: non-stenotic segment: 0.26 (0.15-0.45) cm/s; stenotic segment: 0.11 (0.09-0.18) cm/s] remained on low magnitudes comparable to HCs. Conclusion: Increased cranio-caudal oscillations of the cervical cord are the cardinal pathophysiologic change and can be quantified using PC-MRI in DCM patients. This study addresses spinal cord oscillations as a relevant biomarker reflecting dynamic mechanical cord stress in DCM patients, potentially contributing to a loss of function.

Assessing walking ability using a robotic gait trainer: opportunities and limitations of assist-as-needed control in spinal cord injury.

BACKGROUND: Walking impairments are a common consequence of neurological disorders and are assessed with clinical scores that suffer from several limitations. Robot-assisted locomotor training is becoming an established clinical practice. Besides training, these devices could be used for assessing walking ability in a controlled environment. Here, we propose an adaptive assist-as-needed (AAN) control for a treadmill-based robotic exoskeleton, the Lokomat, that reduces the support of the device (body weight support and impedance of the robotic joints) based on the ability of the patient to follow a gait pattern displayed on screen. We hypothesize that the converged values of robotic support provide valid and reliable information about individuals' walking ability. METHODS: Fifteen participants with spinal cord injury and twelve controls used the AAN software in the Lokomat twice within a week and were assessed using clinical scores (10MWT, TUG). We used a regression method to identify the robotic measure that could provide the most relevant information about walking ability and determined the test-retest reliability. We also checked whether this result could be extrapolated to non-ambulatory and to unimpaired subjects. RESULTS: The AAN controller could be used in patients with different injury severity levels. A linear model based on one variable (robotic knee stiffness at terminal swing) could explain 74% of the variance in the 10MWT and 61% in the TUG in ambulatory patients and showed good relative reliability but poor absolute reliability. Adding the variable 'maximum hip flexor torque' to the model increased the explained variance above 85%. This did not extend to non-ambulatory nor to able-bodied individuals, where variables related to stance phase and to push-off phase seem more relevant. CONCLUSIONS: The novel AAN software for the Lokomat can be used to quantify the support required by a patient while performing robotic gait training. The adaptive software might enable more challenging training conditions tuned to the ability of the individuals. While the current implementation is not ready for assessment in clinical practice, we could demonstrate that this approach is safe, and it could be integrated as assist-as-needed training, rather than as assessment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02425332.

Development of a Sham Protocol to Investigate Transcutaneous Tibial Nerve Stimulation in Randomised, Sham-Controlled, Double-Blind Clinical Trials.

Transcutaneous tibial nerve stimulation (TTNS) is a promising treatment for neurogenic lower urinary tract symptoms. However, the evidence is limited due to a general lack of randomised controlled trials (RCTs) and, also, inconsistency in the sham and blinding conditions. In the context of much-needed RCTs, we aimed to develop a suitable sham-control protocol for a clinical setting to maintain blinding but avoid meaningful stimulation of the tibial nerve. Three potential electrode positions (lateral malleolus/5th metatarsal/plantar calcaneus) and two electrode sizes (diameter: 2.5 cm/3.2 cm) were tested to determine which combination provided the optimal sham configuration for a TTNS approach, based on a visible motor response. Sixteen healthy volunteers underwent sensory and motor assessments for each sham configuration. Eight out of them came back for an extra TTNS visit. Sensory thresholds were present for all sham configurations, with linear regression models revealing a significant effect regarding electrode position (highest at plantar calcaneus) but not size. In addition, motor thresholds varied with the position-lowest for the 5th metatarsal. Only using this position and 3.2 cm electrodes attained a 100% response rate. Compared to TTNS, sensory and motor thresholds were generally higher for the sham configurations; meanwhile, perceived pain was only higher at the lateral malleolus. In conclusion, using the 5th metatarsal position and 3.2 cm electrodes proved to be the most suitable sham configuration. Implemented as a four-electrode setup with standardized procedures, this appears to be a suitable RCT protocol for maintaining blinding and controlling for nonspecific TTNS effects in a clinical setting.

Priming of the autonomic nervous system after an experimental human pain model.

Modulated autonomic responses to noxious stimulation have been reported in experimental and clinical pain. These effects are likely mediated by nociceptive sensitization, but may also, more simply reflect increased stimulus-associated arousal. To disentangle between sensitization- and arousal-mediated effects on autonomic responses to noxious input, we recorded sympathetic skin responses (SSRs) in response to 10 pinprick and heat stimuli before (PRE) and after (POST) an experimental heat pain model to induce secondary hyperalgesia (EXP) and a control model (CTRL) in 20 healthy females. Pinprick and heat stimuli were individually adapted for pain perception (4/10) across all assessments. Heart rate, heart rate variability, and skin conductance level (SCL) were assessed before, during, and after the experimental heat pain model. Both pinprick- and heat-induced SSRs habituated from PRE to POST in CTRL, but not EXP (P = 0.033). Background SCL (during stimuli application) was heightened in EXP compared with CTRL condition during pinprick and heat stimuli (P = 0.009). Our findings indicate that enhanced SSRs after an experimental pain model are neither fully related to subjective pain, as SSRs dissociated from perceptual responses, nor to nociceptive sensitization, as SSRs were enhanced for both modalities. Our findings can, however, be explained by priming of the autonomic nervous system during the experimental pain model, which makes the autonomic nervous system more susceptible to noxious input. Taken together, autonomic readouts have the potential to objectively assess not only nociceptive sensitization but also priming of the autonomic nervous system, which may be involved in the generation of distinct clinical pain phenotypes.NEW & NOTEWORTHY The facilitation of pain-induced sympathetic skin responses observed after experimentally induced central sensitization is unspecific to the stimulation modality and thereby unlikely solely driven by nociceptive sensitization. In addition, these enhanced pain-induced autonomic responses are also not related to higher stimulus-associated arousal, but rather a general priming of the autonomic nervous system. Hence, autonomic readouts may be able to detect generalized hyperexcitability in chronic pain, beyond the nociceptive system, which may contribute to clinical pain phenotypes.

Intrinsic brain connectivity alterations despite intact pain inhibition in subjects with neuropathic pain after spinal cord injury: a pilot study.

Endogenous pain modulation in humans is frequently investigated with conditioned pain modulation (CPM). Deficient pain inhibition is a proposed mechanism that contributes to neuropathic pain (NP) after spinal cord injury (SCI). Recent studies have combined CPM testing and neuroimaging to reveal neural correlates of CPM efficiency in chronic pain. This study investigated differences in CPM efficiency in relation to resting-state functional connectivity (rsFC) between 12 SCI-NP subjects and 13 age- and sex-matched healthy controls (HC). Twelve and 11 SCI-NP subjects were included in psychophysical and rsFC analyses, respectively. All HC were included in the final analyses. Psychophysical readouts were analysed to determine CPM efficiency within and between cohorts. Group differences of rsFC, in relation to CPM efficiency, were explored with seed-to-voxel rsFC analyses with pain modulatory regions, e.g. ventrolateral periaqueductal gray (vlPAG) and amygdala. Overall, pain inhibition was not deficient in SCI-NP subjects and was greater in those with more intense NP. Greater pain inhibition was associated with weaker rsFC between the vlPAG and amygdala with the visual and frontal cortex, respectively, in SCI-NP subjects but with stronger rsFC in HC. Taken together, SCI-NP subjects present with intact pain inhibition, but can be differentiated from HC by an inverse relationship between CPM efficiency and intrinsic connectivity of supraspinal regions. Future studies with larger cohorts are necessary to consolidate the findings in this study.

The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study.

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.

Intramuscular coherence enables robust assessment of modulated supra-spinal input in human gait: an inter-dependence study of visual task and walking speed.

Intramuscular high-frequency coherence is increased during visually guided treadmill walking as a consequence of increased supra-spinal input. The influence of walking speed on intramuscular coherence and its inter-trial reproducibility need to be established before adoption as a functional gait assessment tool in clinical settings. Here, fifteen healthy controls performed a normal and a target walking task on a treadmill at various speeds (0.3 m/s, 0.5 m/s, 0.9 m/s, and preferred) during two sessions. Intramuscular coherence was calculated between two surface EMG recordings sites of the Tibialis anterior muscle during the swing phase of walking. The results were averaged across low-frequency (5-14 Hz) and high-frequency (15-55 Hz) bands. The effect of speed, task, and time on mean coherence was assessed using three-way repeated measures ANOVA. Reliability and agreement were calculated with the intra-class correlation coefficient and Bland-Altman method, respectively. Intramuscular coherence during target walking was significantly higher than during normal walking across all walking speeds in the high-frequency band as obtained by the three-way repeated measures ANOVA. Interaction effects between task and speed were found for the low- and high-frequency bands, suggesting that task-dependent differences increase at higher walking speeds. Reliability of intramuscular coherence was moderate to excellent for most normal and target walking tasks in all frequency bands. This study confirms previous reports of increased intramuscular coherence during target walking, while providing first evidence for reproducibility and robustness of this measure as a requirement to investigate supra-spinal input.Trial registration Registry number/ClinicalTrials.gov Identifier: NCT03343132, date of registration 2017/11/17.

Walking Outcome After Traumatic Paraplegic Spinal Cord Injury: The Function of Which Myotomes Makes a Difference?

BACKGROUND: Accurate prediction of walking function after a traumatic spinal cord injury (SCI) is crucial for an appropriate tailoring and application of therapeutical interventions. Long-term outcome of ambulation is strongly related to residual muscle function acutely after injury and its recovery potential. The identification of the underlying determinants of ambulation, however, remains a challenging task in SCI, a neurological disorder presented with heterogeneous clinical manifestations and recovery trajectories. OBJECTIVES: Stratification of walking function and determination of its most relevant underlying muscle functions based on stratified homogeneous patient subgroups. METHODS: Data from individuals with paraplegic SCI were used to develop a prediction-based stratification model, applying unbiased recursive partitioning conditional inference tree (URP-CTREE). The primary outcome was the 6-minute walk test at 6 months after injury. Standardized neurological assessments ≤15 days after injury were chosen as predictors. Resulting subgroups were incorporated into a subsequent node-specific analysis to attribute the role of individual lower extremity myotomes for the prognosis of walking function. RESULTS: Using URP-CTREE, the study group of 361 SCI patients was divided into 8 homogeneous subgroups. The node specific analysis uncovered that proximal myotomes L2 and L3 were driving factors for the differentiation between walkers and non-walkers. Distal myotomes L4-S1 were revealed to be responsible for the prognostic distinction of indoor and outdoor walkers (with and without aids). CONCLUSION: Stratification of a heterogeneous population with paraplegic SCI into more homogeneous subgroups, combined with the identification of underlying muscle functions prospectively determining the walking outcome, enable potential benefit for application in clinical trials and practice.

Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury.

BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane. METHODS: This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored. RESULTS: Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier. DISCUSSION: This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes.

Data-driven characterization of walking after a spinal cord injury using inertial sensors.

BACKGROUND: An incomplete spinal cord injury (SCI) refers to remaining sensorimotor function below the injury with the possibility for the patient to regain walking abilities. However, these patients often suffer from diverse gait deficits, which are not objectively assessed in the current clinical routine. Wearable inertial sensors are a promising tool to capture gait patterns objectively and started to gain ground for other neurological disorders such as stroke, multiple sclerosis, and Parkinson's disease. In this work, we present a data-driven approach to assess walking for SCI patients based on sensor-derived outcome measures. We aimed to (i) characterize their walking pattern in more depth by identifying groups with similar walking characteristics and (ii) use sensor-derived gait parameters as predictors for future walking capacity. METHODS: The dataset analyzed consisted of 66 SCI patients and 20 healthy controls performing a standardized gait test, namely the 6-min walking test (6MWT), while wearing a sparse sensor setup of one sensor attached to each ankle. A data-driven approach has been followed using statistical methods and machine learning models to identify relevant and non-redundant gait parameters. RESULTS: Clustering resulted in 4 groups of patients that were compared to each other and to the healthy controls. The clusters did differ in terms of their average walking speed but also in terms of more qualitative gait parameters such as variability or parameters indicating compensatory movements. Further, using longitudinal data from a subset of patients that performed the 6MWT several times during their rehabilitation, a prediction model has been trained to estimate whether the patient's walking speed will improve significantly in the future. Including sensor-derived gait parameters as inputs for the prediction model resulted in an accuracy of 80%, which is a considerable improvement of 10% compared to using only the days since injury, the present 6MWT distance, and the days until the next 6MWT as predictors. CONCLUSIONS: In summary, the work presented proves that sensor-derived gait parameters provide additional information on walking characteristics and thus are beneficial to complement clinical walking assessments of SCI patients. This work is a step towards a more deficit-oriented therapy and paves the way for better rehabilitation outcome predictions.

Queckenstedt's test repurposed for the quantitative assessment of the cerebrospinal fluid pulsatility curve.

PURPOSE: Before the era of spinal imaging, presence of a spinal canal block was tested through gross changes in cerebrospinal fluid pressure (CSFP) provoked by manual compression of the jugular veins (referred to as Queckenstedt's test; QT). Beyond these provoked gross changes, cardiac-driven CSFP peak-to-valley amplitudes (CSFPp) can be recorded during CSFP registration. This is the first study to assess whether the QT can be repurposed to derive descriptors of the CSF pulsatility curve, focusing on feasibility and repeatability. METHOD: Lumbar puncture was performed in lateral recumbent position in fourteen elderly patients (59.7±9.3 years, 6F) (NCT02170155) without stenosis of the spinal canal. CSFP was recorded during resting state and QT. A surrogate for the relative pulse pressure coefficient was computed from repeated QTs (i.e., RPPC-Q). RESULTS: Resting state mean CSFP was 12.3 mmHg (IQR 3.2) and CSFPp was 1.0 mmHg (0.5). Mean CSFP rise during QT was 12.5 mmHg (7.3). CSFPp showed an average 3-fold increase at peak QT compared to the resting state. Median RPPC-Q was 0.18 (0.04). There was no systematic error in the computed metrics between the first and second QT. CONCLUSION: This technical note describes a method to reliably derive, beyond gross CSFP increments, metrics related to cardiac-driven amplitudes during QT (i.e., RPPC-Q). A study comparing these metrics as obtained by established procedures (i.e., infusion testing) and by QT is warranted.