Intramuscular coherence during challenging walking in incomplete spinal cord injury: Reduced high-frequency coherence reflects impaired supra-spinal control

Individuals regaining reliable day-to-day walking function after incomplete spinal cord injury (iSCI) report persisting unsteadiness when confronted with walking challenges. However, quantifiable measures of walking capacity lack the sensitivity to reveal underlying impairments of supra-spinal locomotor control. This study investigates the relationship between intramuscular coherence and corticospinal dynamic balance control during a visually guided Target walking treadmill task. In thirteen individuals with iSCI and 24 controls, intramuscular coherence and cumulant densities were estimated from pairs of Tibialis anterior surface EMG recordings during normal treadmill walking and a Target walking task. The approximate center of mass was calculated from pelvis markers. Spearman rank correlations were performed to evaluate the relationship between intramuscular coherence, clinical parameters, and center of mass parameters. In controls, we found that the Target walking task results in increased high-frequency (21-44 Hz) intramuscular coherence, which negatively related to changes in the center of mass movement, whereas this modulation was largely reduced in individuals with iSCI. The impaired modulation of high-frequency intramuscular coherence during the Target walking task correlated with neurophysiological and functional readouts, such as motor-evoked potential amplitude and outdoor mobility score, as well as center of mass trajectory length. The Target walking effect, the difference between Target and Normal walking intramuscular coherence, was significantly higher in controls than in individuals with iSCI [F(1.0,35.0) = 13.042, p < 0.001]. Intramuscular coherence obtained during challenging walking in individuals with iSCI may provide information on corticospinal gait control. The relationships between biomechanics, clinical scores, and neurophysiology suggest that intramuscular coherence assessed during challenging tasks may be meaningful for understanding impaired supra-spinal control in individuals with iSCI

Mind your step : Target walking task reveals gait disturbance in individuals with incomplete spinal cord injury

BACKGROUND: Walking over obstacles requires precise foot placement while maintaining balance control of the center of mass (CoM) and the flexibility to adapt the gait patterns. Most individuals with incomplete spinal cord injury (iSCI) are capable of overground walking on level ground; however, gait stability and adaptation may be compromised. CoM control was investigated during a challenging target walking (TW) task in individuals with iSCI compared to healthy controls. The hypothesis was that individuals with iSCI, when challenged with TW, show a lack of gait pattern adaptability which is reflected by an impaired adaptation of CoM movement compared to healthy controls. METHODS: A single-center controlled diagnostic clinical trial with thirteen participants with iSCI (0.3-24 years post injury; one subacute and twelve chronic) and twelve healthy controls was conducted where foot and pelvis kinematics were acquired during two conditions: normal treadmill walking (NW) and visually guided target walking (TW) with handrail support, during which participants stepped onto projected virtual targets synchronized with the moving treadmill surface. Approximated CoM was calculated from pelvis markers and used to calculate CoM trajectory length and mean CoM Euclidean distance TW-NW (primary outcome). Nonparametric statistics, including spearman rank correlations, were performed to evaluate the relationship between clinical parameter, outdoor mobility score, performance, and CoM parameters (secondary outcome). RESULTS: Healthy controls adapted to TW by decreasing anterior-posterior and vertical CoM trajectory length (p < 0.001), whereas participants with iSCI reduced CoM trajectory length only in the vertical direction (p = 0.002). Mean CoM Euclidean distance TW-NW correlated with participants' neurological level of injury (R = 0.76, p = 0.002) and CoM trajectory length (during TW) correlated with outdoor mobility score (R = - 0.64, p = 0.026). CONCLUSIONS: This study demonstrated that reduction of CoM movement is a common strategy to cope with TW challenge in controls, but it is impaired in individuals with iSCI. In the iSCI group, the ability to cope with gait challenges worsened the more rostral the level of injury. Thus, the TW task could be used as a gait challenge paradigm in ambulatory iSCI individuals. Trial registration Registry number/ ClinicalTrials.gov Identifier: NCT03343132, date of registration 2017/11/17

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Mind your step: Target walking task reveals gait disturbance in individuals with incomplete spinal cord injury

BACKGROUND Walking over obstacles requires precise foot placement while maintaining balance control of the center of mass (CoM) and the flexibility to adapt the gait patterns. Most individuals with incomplete spinal cord injury (iSCI) are capable of overground walking on level ground; however, gait stability and adaptation may be compromised. CoM control was investigated during a challenging target walking (TW) task in individuals with iSCI compared to healthy controls. The hypothesis was that individuals with iSCI, when challenged with TW, show a lack of gait pattern adaptability which is reflected by an impaired adaptation of CoM movement compared to healthy controls. METHODS A single-center controlled diagnostic clinical trial with thirteen participants with iSCI (0.3-24 years post injury; one subacute and twelve chronic) and twelve healthy controls was conducted where foot and pelvis kinematics were acquired during two conditions: normal treadmill walking (NW) and visually guided target walking (TW) with handrail support, during which participants stepped onto projected virtual targets synchronized with the moving treadmill surface. Approximated CoM was calculated from pelvis markers and used to calculate CoM trajectory length and mean CoM Euclidean distance TW-NW (primary outcome). Nonparametric statistics, including spearman rank correlations, were performed to evaluate the relationship between clinical parameter, outdoor mobility score, performance, and CoM parameters (secondary outcome). RESULTS Healthy controls adapted to TW by decreasing anterior-posterior and vertical CoM trajectory length (p < 0.001), whereas participants with iSCI reduced CoM trajectory length only in the vertical direction (p = 0.002). Mean CoM Euclidean distance TW-NW correlated with participants' neurological level of injury (R = 0.76, p = 0.002) and CoM trajectory length (during TW) correlated with outdoor mobility score (R = - 0.64, p = 0.026). CONCLUSIONS This study demonstrated that reduction of CoM movement is a common strategy to cope with TW challenge in controls, but it is impaired in individuals with iSCI. In the iSCI group, the ability to cope with gait challenges worsened the more rostral the level of injury. Thus, the TW task could be used as a gait challenge paradigm in ambulatory iSCI individuals. Trial registration Registry number/ ClinicalTrials.gov Identifier: NCT03343132, date of registration 2017/11/17

Triggers for freezing of gait in individuals with Parkinson's disease: a systematic review

BackgroundFreezing of Gait (FOG) is a motor symptom frequently observed in advanced Parkinson's disease. However, due to its paroxysmal nature and diverse presentation, assessing FOG in a clinical setting can be challenging. Before FOG can be fully investigated, it is critical that a reliable experimental setting is established in which FOG can be evoked in a standardized manner, but the efficacy of various gait tasks and triggers for eliciting FOG remains unclear.ObjectivesThis study aimed to conduct a systematic review of the existing literature and evaluate the available evidence for the relationship between specific motor tasks, triggers, and FOG episodes in individuals with Parkinson's disease (PwPD).MethodsWe conducted a literature search on four online databases (PubMed, Web of Science, EMBASE, and Cochrane Library) using the keywords "Parkinson's disease," "Freezing of Gait", "triggers" and "tasks". A total of 128 articles met the inclusion criteria and were included in our analysis.ResultsThe review found that a wide range of gait tasks were employed in studies assessing FOG among PD patients. However, three tasks (turning, dual tasking, and straight walking) emerged as the most frequently used. Turning (28%) appears to be the most effective trigger for eliciting FOG in PwPD, followed by walking through a doorway (14%) and dual tasking (10%).ConclusionThis review thereby supports the utilisation of turning, especially a 360-degree turn, as a reliable trigger for FOG in PwPD. This finding could be beneficial to clinicians conducting clinical evaluations and researchers aiming to assess FOG in a laboratory environment.ISSN:1664-229

Intramuscular coherence during challenging walking in incomplete spinal cord injury : Reduced high-frequency coherence reflects impaired supra-spinal control

Individuals regaining reliable day-to-day walking function after incomplete spinal cord injury (iSCI) report persisting unsteadiness when confronted with walking challenges. However, quantifiable measures of walking capacity lack the sensitivity to reveal underlying impairments of supra-spinal locomotor control. This study investigates the relationship between intramuscular coherence and corticospinal dynamic balance control during a visually guided Target walking treadmill task. In thirteen individuals with iSCI and 24 controls, intramuscular coherence and cumulant densities were estimated from pairs of Tibialis anterior surface EMG recordings during normal treadmill walking and a Target walking task. The approximate center of mass was calculated from pelvis markers. Spearman rank correlations were performed to evaluate the relationship between intramuscular coherence, clinical parameters, and center of mass parameters. In controls, we found that the Target walking task results in increased high-frequency (21-44 Hz) intramuscular coherence, which negatively related to changes in the center of mass movement, whereas this modulation was largely reduced in individuals with iSCI. The impaired modulation of high-frequency intramuscular coherence during the Target walking task correlated with neurophysiological and functional readouts, such as motor-evoked potential amplitude and outdoor mobility score, as well as center of mass trajectory length. The Target walking effect, the difference between Target and Normal walking intramuscular coherence, was significantly higher in controls than in individuals with iSCI [F(1.0,35.0) = 13.042, p < 0.001]. Intramuscular coherence obtained during challenging walking in individuals with iSCI may provide information on corticospinal gait control. The relationships between biomechanics, clinical scores, and neurophysiology suggest that intramuscular coherence assessed during challenging tasks may be meaningful for understanding impaired supra-spinal control in individuals with iSCI

Gamification of Physical Therapy Exercises Using Commercial Entertainment Content: A Safety and Feasibility Study

Independent physiotherapy at home is a crucial element of rehabilitative care for a wide range of conditions as it constitutes a large portion of the overall therapy dose. However, up to 80% of individuals who are prescribed at-home physiotherapy do not consistently adhere to their treatment schedule, resulting in poor treatment outcomes. This is likely due to a lack of motivation and progress tracking in the current standard of care. We have developed a novel software prototype that allows users to control commercial entertainment content, such as video games or interactive music videos, with their movements during physiotherapy. By connecting therapy to proven entertainment content, we aim to improve on the current motivational deficits. This study investigated the safety and feasibility of this concept in a controlled environment over four physical therapy sessions with seven patients suffering from musculoskeletal and neurological conditions. As a secondary outcome, patients were asked about their enjoyment, perceived competence and effort using the Intrinsic Motivation Inventory (IMI) questionnaire. All participants were able to interact with the presented entertainment content and completed the study with no adverse events. Despite the diversity in pathology, age and training scenarios, the entertainment content maintained the patients' enjoyment with a high average rate of 6/7 on the IMI scale. Interacting with commercial entertainment content by doing physical therapy exercises was feasible, safe, and well-received over the six-week study period

Lower extremity outcome measures: considerations for clinical trials in spinal cord injury

STUDY DESIGN This is a focused review article. OBJECTIVES To identify important concepts in lower extremity (LE) assessment with a focus on locomotor outcomes and provide guidance on how existing outcome measurement tools may be best used to assess experimental therapies in spinal cord injury (SCI). The emphasis lies on LE outcomes in individuals with complete and incomplete SCI in Phase II-III trials. METHODS This review includes a summary of topics discussed during a workshop focusing on LE function in SCI, conceptual discussion of corresponding outcome measures and additional focused literature review. RESULTS There are a number of sensitive, accurate, and responsive outcome tools measuring both quantitative and qualitative aspects of LE function. However, in trials with individuals with very acute injuries, a baseline assessment of the primary (or secondary) LE outcome measure is often not feasible. CONCLUSION There is no single outcome measure to assess all individuals with SCI that can be used to monitor changes in LE function regardless of severity and level of injury. Surrogate markers have to be used to assess LE function in individuals with severe SCI. However, it is generally agreed that a direct measurement of the performance for an appropriate functional activity supersedes any surrogate marker. LE assessments have to be refined so they can be used across all time points after SCI, regardless of the level or severity of spinal injury. SPONSORS Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor