Validity and reliability of the 2-minute walk test in individuals with spinal cord injury.

STUDY DESIGN: Multicentre-observational study. OBJECTIVES: The 6-minute walk test (6mWT) is an established assessment of walking function in individuals with spinal cord injury (SCI). However, walking 6 min can be demanding for severely impaired individuals. The 2-minute walk test (2mWT) could be an appropriate alternative that has already been validated in other neurological disorders. The aim of this study was to assess construct validity and test-rest reliability of the 2mWT in individuals with SCI. In addition, the influence of walking performance on sensitivity to change of the 2mWT was assessed. SETTING: Swiss Paraplegic Center Nottwil, Switzerland; Balgrist University Hospital, Zürich, Switzerland. METHODS: Fifty individuals (aged 18-79) with SCI (neurological level of injury: C1-L3, AIS: A-D) were assessed on two test days separated by 1 to 7 days. The first assessment consisted of a 2mWT familiarization, followed by a 2mWT and 10-meter walk test (10MWT) (including the Walking Index for Spinal Cord Injury (WISCI II)) in randomized order. The second assessment consisted of 2mWT and 6mWT in randomized order. Tests were separated by at least 30 min of rest. RESULTS: The interclass correlation coefficient between the 2mWT assessed on the first and second test day was excellent (r = 0.980, p < 0.001). The 2mWT correlated very strongly with the 6mWT (r = 0.992, p < 0.001) and the 10MWT (r = 0.964, p < 0.001), and moderately with the WISCI II (r = 0.571, p < 0.001). Sensitivity to change was slightly affected by walking performance. CONCLUSION: The 2mWT is a valid and reliable alternative to the 6mWT to measure walking function in individuals with SCI. TRIAL REGISTRATION: NCT04555759.

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.

Real-time motion onset recognition for robot-assisted gait rehabilitation.

BACKGROUND: Many patients with neurological movement disorders fear to fall while performing postural transitions without assistance, which prevents them from participating in daily life. To overcome this limitation, multi-directional Body Weight Support (BWS) systems have been developed allowing them to perform training in a safe environment. In addition to overground walking, these innovative/novel systems can assist patients to train many more gait-related tasks needed for daily life under very realistic conditions. The necessary assistance during the users' movements can be provided via task-dependent support designs. One remaining challenge is the manual switching between task-dependent supports. It is error-prone, cumbersome, distracts therapists and patients, and interrupts the training workflow. Hence, we propose a real-time motion onset recognition model that performs automatic support switching between standing-up and sitting-down transitions and other gait-related tasks (8 classes in total). METHODS: To predict the onsets of the gait-related tasks, three Inertial Measurement Units (IMUs) were attached to the sternum and middle of outer thighs of 19 controls without neurological movement disorders and two individuals with incomplete Spinal Cord Injury (iSCI). The data of IMUs obtained from different gait tasks was sent synchronously to a real-time data acquisition system through a custom-made Bluetooth-EtherCAT gateway. In the first step, data was applied offline for training five different classifiers. The best classifier was chosen based on F1-score results of a Leave-One-Participant-Out Cross-Validation (LOPOCV), which is an unbiased way of testing. In a final step, the chosen classifier was tested in real time with an additional control participant to demonstrate feasibility for real-time classification. RESULTS: Testing five different classifiers, the best performance was obtained in a single-layer neural network with 25 neurons. The F1-score of [Formula: see text] and [Formula: see text] are achieved on testing using LOPOCV and test data ([Formula: see text], participants = 20), respectively. Furthermore, the results from the implemented real-time classifier were compared with the offline classifier and revealed nearly identical performance (difference = [Formula: see text]). CONCLUSIONS: A neural network classifier was trained for identifying the onset of gait-related tasks in real time. Test data showed convincing performance for offline and real-time classification. This demonstrates the feasibility and potential for implementing real-time onset recognition in rehabilitation devices in future.

Validation of Non-Restrictive Inertial Gait Analysis of Individuals with Incomplete Spinal Cord Injury in Clinical Settings.

Inertial Measurement Units (IMUs) have gained popularity in gait analysis and human motion tracking, and they provide certain advantages over stationary line-of-sight-dependent Optical Motion Capture (OMC) systems. IMUs appear as an appropriate alternative solution to reduce dependency on bulky, room-based hardware and facilitate the analysis of walking patterns in clinical settings and daily life activities. However, most inertial gait analysis methods are unpractical in clinical settings due to the necessity of precise sensor placement, the need for well-performed calibration movements and poses, and due to distorted magnetometer data in indoor environments as well as nearby ferromagnetic material and electronic devices. To address these limitations, recent literature has proposed methods for self-calibrating magnetometer-free inertial motion tracking, and acceptable performance has been achieved in mechanical joints and in individuals without neurological disorders. However, the performance of such methods has not been validated in clinical settings for individuals with neurological disorders, specifically individuals with incomplete Spinal Cord Injury (iSCI). In the present study, we used recently proposed inertial motion-tracking methods, which avoid magnetometer data and leverage kinematic constraints for anatomical calibration. We used these methods to determine the range of motion of the Flexion/Extension (F/E) hip and Abduction/Adduction (A/A) angles, the F/E knee angles, and the Dorsi/Plantar (D/P) flexion ankle joint angles during walking. Data (IMU and OMC) of five individuals with no neurological disorders (control group) and five participants with iSCI walking for two minutes on a treadmill in a self-paced mode were analyzed. For validation purposes, the OMC system was considered as a reference. The mean absolute difference (MAD) between calculated range of motion of joint angles was 5.00°, 5.02°, 5.26°, and 3.72° for hip F/E, hip A/A, knee F/E, and ankle D/P flexion angles, respectively. In addition, relative stance, swing, double support phases, and cadence were calculated and validated. The MAD for the relative gait phases (stance, swing, and double support) was 1.7%, and the average cadence error was 0.09 steps/min. The MAD values for RoM and relative gait phases can be considered as clinically acceptable. Therefore, we conclude that the proposed methodology is promising, enabling non-restrictive inertial gait analysis in clinical settings.

Protein phosphatase 2A holoenzymes regulate leucine-rich repeat kinase 2 phosphorylation and accumulation.

LRRK2 is a highly phosphorylated multidomain protein and mutations in the gene encoding LRRK2 are a major genetic determinant of Parkinson's disease (PD). Dephosphorylation at LRRK2's S910/S935/S955/S973 phosphosite cluster is observed in several conditions including in sporadic PD brain, in several disease mutant forms of LRRK2 and after pharmacological LRRK2 kinase inhibition. However, the mechanism of LRRK2 dephosphorylation is poorly understood. We performed a phosphatome-wide reverse genetics screen to identify phosphatases involved in the dephosphorylation of the LRRK2 phosphosite S935. Candidate phosphatases selected from the primary screen were tested in mammalian cells, Xenopus oocytes and in vitro. Effects of PP2A on endogenous LRRK2 phosphorylation were examined via expression modulation with CRISPR/dCas9. Our screening revealed LRRK2 phosphorylation regulators linked to the PP1 and PP2A holoenzyme complexes as well as CDC25 phosphatases. We showed that dephosphorylation induced by different kinase inhibitor triggered relocalisation of phosphatases PP1 and PP2A in LRRK2 subcellular compartments in HEK-293 T cells. We also demonstrated that LRRK2 is an authentic substrate of PP2A both in vitro and in Xenopus oocytes. We singled out the PP2A holoenzyme PPP2CA:PPP2R2 as a powerful phosphoregulator of pS935-LRRK2. Furthermore, we demonstrated that this specific PP2A holoenzyme induces LRRK2 relocalization and triggers LRRK2 ubiquitination, suggesting its involvement in LRRK2 clearance. The identification of the PPP2CA:PPP2R2 complex regulating LRRK2 S910/S935/S955/S973 phosphorylation paves the way for studies refining PD therapeutic strategies that impact LRRK2 phosphorylation.

Repeated assessment of key clinical walking measures can induce confounding practice effects.

Accurate functional outcome measures are critical for both clinical trials and routine patient assessments. Many functional outcomes improve with test repetition, a phenomenon that can confound the findings of longitudinal assessments. In this viewpoint, we tackle the poorly considered issue of practice effects in prevailing clinical walking tests based on current literature, while also presenting the original data from our own work, in which we investigated practice effects in the timed 25-foot walk (T25FW), timed-up and go (TUG), and 2-minute walk test (2MWT). In these tests, performed on 3 consecutive days in 10 patients with multiple sclerosis and 40 healthy controls, we observed significant practice effects in several established walking outcomes, including a 9.0% improvement in patients' TUG performance (p = 0.0146). Pre-training in these walking tests prior to baseline measurement may mitigate practice effects, thereby improving the accuracy and value of their repeated use in research and clinical settings.

LRRK2-mediated Rab10 phosphorylation in immune cells from Parkinson's disease patients.

BACKGROUND: Leucine-rich repeat kinase 2 is a potential therapeutic target for the treatment of Parkinson's disease, and clinical trials of leucine-rich repeat kinase 2 inhibitors are in development. The objective of this study was to evaluate phosphorylation of a new leucine-rich repeat kinase 2 substrate, Rab10, for potential use as a target engagement biomarker and/or patient enrichment biomarker for leucine-rich repeat kinase 2 inhibitor clinical trials. METHODS: Peripheral blood mononuclear cells and neutrophils were isolated from Parkinson's disease patients and matched controls, and treated ex vivo with a leucine-rich repeat kinase 2 inhibitor. Immunoblotting was used to measure levels of leucine-rich repeat kinase 2 and Rab10 and their phosphorylation. Plasma inflammatory cytokines were measured by multiplex enzyme-linked immunosorbent assay. RESULTS: Mononuclear cells and neutrophils of both controls and Parkinson's disease patients responded the same to leucine-rich repeat kinase 2 inhibitor treatment. Leucine-rich repeat kinase 2 levels in mononuclear cells were the same in controls and Parkinson's disease patients, whereas leucine-rich repeat kinase 2 was significantly increased in Parkinson's disease neutrophils. Rab10 T73 phosphorylation levels were similar in controls and Parkinson's disease patients and did not correlate with leucine-rich repeat kinase 2 levels. Immune-cell levels of leucine-rich repeat kinase 2 and Rab10 T73 phosphorylation were associated with plasma inflammatory cytokine levels. CONCLUSIONS: Rab10 T73 phosphorylation appears to be a valid target engagement biomarker for potential use in leucine-rich repeat kinase 2 inhibitor clinical trials. However, a lack of association between leucine-rich repeat kinase 2 and Rab10 phosphorylation complicates the potential use of Rab10 phosphorylation as a patient enrichment biomarker. Although replication is required, increased leucine-rich repeat kinase 2 levels in neutrophils from Parkinson's disease patients may have the potential for patient stratification. leucine-rich repeat kinase 2 activity in peripheral immune cells may contribute to an inflammatory phenotype. © 2018 International Parkinson and Movement Disorder Society.

P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity.

Autosomal-dominant, missense mutations in the leucine-rich repeat protein kinase 2 (LRRK2) gene are the most common genetic predisposition to develop Parkinson's disease (PD). LRRK2 kinase activity is increased in several pathogenic mutations (N1437H, R1441C/G/H, Y1699C, G2019S), implicating hyperphosphorylation of a substrate in the pathogenesis of the disease. Identification of the downstream targets of LRRK2 is a crucial endeavor in the field to understand LRRK2 pathway dysfunction in the disease. We have identified the signaling adapter protein p62/SQSTM1 as a novel endogenous interacting partner and a substrate of LRRK2. Using mass spectrometry and phospho-specific antibodies, we found that LRRK2 phosphorylates p62 on Thr138 in vitro and in cells. We found that the pathogenic LRRK2 PD-associated mutations (N1437H, R1441C/G/H, Y1699C, G2019S) increase phosphorylation of p62 similar to previously reported substrate Rab proteins. Notably, we found that the pathogenic I2020T mutation and the risk factor mutation G2385R displayed decreased phosphorylation of p62. p62 phosphorylation by LRRK2 is blocked by treatment with selective LRRK2 inhibitors in cells. We also found that the amino-terminus of LRRK2 is crucial for optimal phosphorylation of Rab7L1 and p62 in cells. LRRK2 phosphorylation of Thr138 is dependent on a p62 functional ubiquitin-binding domain at its carboxy-terminus. Co-expression of p62 with LRRK2 G2019S increases the neurotoxicity of this mutation in a manner dependent on Thr138. p62 is an additional novel substrate of LRRK2 that regulates its toxic biology, reveals novel signaling nodes and can be used as a pharmacodynamic marker for LRRK2 kinase activity.

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.

Overground walking patterns after chronic incomplete spinal cord injury show distinct response patterns to unloading.

BACKGROUND: Body weight support (BWS) is often provided to incomplete spinal cord injury (iSCI) patients during rehabilitation to enable gait training before full weight-bearing is recovered. Emerging robotic devices enable BWS during overground walking, increasing task-specificity of the locomotor training. However, in contrast to a treadmill setting, there is little information on how unloading is integrated into overground locomotion. We investigated the effect of a transparent multi-directional BWS system on overground walking patterns at different levels of unloading in individuals with chronic iSCI (CiSCI) compared to controls. METHODS: Kinematics of 12 CiSCI were analyzed at six different BWS levels from 0 to 50% body weight unloading during overground walking at 2kmh- 1 and compared to speed-matched controls. RESULTS: In controls, temporal parameters, single joint trajectories, and intralimb coordination responded proportionally to the level of unloading, while spatial parameters remained unaffected. In CiSCI, unloading induced similar changes in temporal parameters. CiSCI, however, did not adapt their intralimb coordination or single joint trajectories to the level of unloading. CONCLUSIONS: The findings revealed that continuous, dynamic unloading during overground walking results in subtle and proportional gait adjustments corresponding to changes in body load. CiSCI demonstrated diminished responses in specific domains of gait, indicating that their altered neural processing impeded the adjustment to environmental constraints. CiSCI retain their movement patterns under overground unloading, indicating that this is a viable locomotor therapy tool that may also offer a potential window on the diminished neural control of intralimb coordination.

LRRK2 levels and phosphorylation in Parkinson's disease brain and cases with restricted Lewy bodies.

BACKGROUND: Leucine rich repeat kinase 2 (LRRK2) is a promising target for the treatment of Parkinson's disease; however, little is known about the expression of LRRK2 in human brain and if/how LRRK2 protein levels are altered in Parkinson's disease. OBJECTIVES: We measured the protein levels of LRRK2 as well as its phosphorylation on serines 910, 935, and 973 in the postmortem brain tissue of Parkinson's disease patients and aged controls with and without Lewy bodies. METHODS: LRRK2 and its phosphorylation were measured by immunoblot in brain regions differentially affected in Parkinson's disease (n = 30) as well as subjects with Lewy bodies restricted to the periphery and lower brain stem (n = 25) and matched controls without pathology (n = 25). RESULTS: LRRK2 levels were increased in cases with restricted Lewy bodies, with a 30% increase measured in the substantia nigra. In clinical Parkinson's disease, levels of LRRK2 negatively correlated to disease duration and were comparable with controls. LRRK2 phosphorylation, however, particularly at serine 935, was reduced with clinical Parkinson's disease with a 36% reduction measured in the substantia nigra. CONCLUSIONS: Our data show that LRRK2 phosphorylation is reduced with clinical PD, whereas LRRK2 expression is increased in early potential prodromal stages. These results contribute to a better understanding of the role of LRRK2 in idiopathic Parkinson's disease and may aid efforts aimed at therapeutically targeting the LRRK2 protein. © 2016 International Parkinson and Movement Disorder Society.

A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.

The G protein-coupled receptor (GPCR) Proteolysis Site (GPS) of cell-adhesion GPCRs and polycystic kidney disease (PKD) proteins constitutes a highly conserved autoproteolysis sequence, but its catalytic mechanism remains unknown. Here, we show that unexpectedly the ∼40-residue GPS motif represents an integral part of a much larger ∼320-residue domain that we termed GPCR-Autoproteolysis INducing (GAIN) domain. Crystal structures of GAIN domains from two distantly related cell-adhesion GPCRs revealed a conserved novel fold in which the GPS motif forms five ß-strands that are tightly integrated into the overall GAIN domain. The GAIN domain is evolutionarily conserved from tetrahymena to mammals, is the only extracellular domain shared by all human cell-adhesion GPCRs and PKD proteins, and is the locus of multiple human disease mutations. Functionally, the GAIN domain is both necessary and sufficient for autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemical environment in the GPS to catalyse peptide bond hydrolysis. Thus, the GAIN domain embodies a unique, evolutionarily ancient and widespread autoproteolytic fold whose function is likely relevant for GPCR signalling and for multiple human diseases.

Chasing central nervous system plasticity: the brainstem's contribution to locomotor recovery in rats with spinal cord injury.

Anatomical plasticity such as fibre growth and the formation of new connections in the cortex and spinal cord is one known mechanism mediating functional recovery after damage to the central nervous system. Little is known about anatomical plasticity in the brainstem, which contains key locomotor regions. We compared changes of the spinal projection pattern of the major descending systems following a cervical unilateral spinal cord hemisection in adult rats. As in humans (Brown-Séquard syndrome), this type of injury resulted in a permanent loss of fine motor control of the ipsilesional fore- and hindlimb, but for basic locomotor functions substantial recovery was observed. Antero- and retrograde tracings revealed spontaneous changes in spinal projections originating from the reticular formation, in particular from the contralesional gigantocellular reticular nucleus: more reticulospinal fibres from the intact hemicord crossed the spinal midline at cervical and lumbar levels. The intact-side rubrospinal tract showed a statistically not significant tendency towards an increased number of midline crossings after injury. In contrast, the corticospinal and the vestibulospinal tract, as well as serotonergic projections, showed little or no side-switching in this lesion paradigm. Spinal adaptations were accompanied by modifications at higher levels of control including side-switching of the input to the gigantocellular reticular nuclei from the mesencephalic locomotor region. Electrolytic microlesioning of one or both gigantocellular reticular nuclei in behaviourally recovered rats led to the reappearance of the impairments observed acutely after the initial injury showing that anatomical plasticity in defined brainstem motor networks contributes significantly to functional recovery after injury of the central nervous system.

Zymogen activation of neurotrypsin and neurotrypsin-dependent agrin cleavage on the cell surface are enhanced by glycosaminoglycans.

The serine peptidase neurotrypsin is stored in presynaptic nerve endings and secreted in an inactive zymogenic form by synaptic activity. After activation, which requires activity of postsynaptic NMDA (N-methyl-D-aspartate) receptors, neurotrypsin cleaves the heparan sulfate proteoglycan agrin at active synapses. The resulting C-terminal 22-kDa fragment of agrin induces dendritic filopodia, which are considered to be precursors of new synapses. In the present study, we investigated the role of GAGs (glycosaminoglycans) in the activation of neurotrypsin and neurotrypsin-dependent agrin cleavage. We found binding of neurotrypsin to the GAG side chains of agrin, which in turn enhanced the activation of neurotrypsin by proprotein convertases and resulted in enhanced agrin cleavage. A similar enhancement of neurotrypsin binding to agrin, neurotrypsin activation and agrin cleavage was induced by the four-amino-acid insert at the y splice site of agrin, which is crucial for the formation of a heparin-binding site. Non-agrin GAGs also contributed to binding and activation of neurotrypsin and, thereby, to agrin cleavage, albeit to a lesser extent. Binding of neurotrypsin to cell-surface glycans locally restricts its conversion from zymogen into active peptidase. This provides the molecular foundation for the local action of neurotrypsin at or in the vicinity of its site of synaptic secretion. By its local action at synapses with correlated pre- and post-synaptic activity, the neurotrypsin-agrin system fulfils the requirements for a mechanism serving experience-dependent modification of activated synapses, which is essential for adaptive structural reorganizations of neuronal circuits in the developing and/or adult brain.

The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins.

C1q-like genes (C1ql1-C1ql4) encode small, secreted proteins that are expressed in differential patterns in the brain but whose receptors and functions remain unknown. BAI3 protein, in contrast, is a member of the cell-adhesion class of G protein-coupled receptors that are expressed at high levels in the brain but whose ligands have thus far escaped identification. Using a biochemical approach, we show that all four C1ql proteins bind to the extracellular thrombospondin-repeat domain of BAI3 with high affinity, and that this binding is mediated by the globular C1q domains of the C1ql proteins. Moreover, we demonstrate that addition of submicromolar concentrations of C1ql proteins to cultured neurons causes a significant decrease in synapse density, and that this decrease was prevented by simultaneous addition of the thrombospondin-repeat fragment of BAI3, which binds to C1ql proteins. Our data suggest that C1ql proteins are secreted signaling molecules that bind to BAI3 and act, at least in part, to regulate synapse formation and/or maintenance.

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.

Profiling locomotor recovery: comprehensive quantification of impairments after CNS damage in rodents.

Rodents are frequently used to model damage and diseases of the central nervous system (CNS) that lead to functional deficits. Impaired locomotor function is currently evaluated by using scoring systems or biomechanical measures. These methods often suffer from limitations such as subjectivity, nonlinearity and low sensitivity, or focus on a few very restricted aspects of movement. Thus, full quantitative profiles of motor deficits after CNS damage are lacking. Here we report the detailed characterization of locomotor impairments after applying common forms of CNS damage in rodents. We obtained many objective and quantitative readouts from rats with either spinal cord injuries or strokes and from transgenic mice (Epha4−/−) during skilled walking, overground walking, wading and swimming, resulting in model-specific locomotor profiles. Our testing and analysis method enables comprehensive assessment of locomotor function in rodents and has broad application in various fields of life science research.

Increasing patient engagement during virtual reality-based motor rehabilitation.

OBJECTIVE: To investigate the influence of different design characteristics of virtual reality exercises on engagement during lower extremity motor rehabilitation. DESIGN: Correlational study. SETTING: Spinal cord injury (SCI) rehabilitation center. PARTICIPANTS: Subjects with SCI (n=12) and control subjects (n=10). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Heart rate and electromyographic activity from both legs at the tibialis anterior, the gastrocnemius medialis, the rectus femoris, and the biceps femoris were recorded. RESULTS: Interactivity (ie, functionally meaningful reactions to motor performance) was crucial for the engagement of subjects. No significant differences in engagement were found between exercises that differed in feedback frequency, explicit task goals, or aspects of competition. CONCLUSIONS: Functional feedback is highly important for the active participation of patients during robotic-assisted rehabilitation. Further investigations on the design characteristics of virtual reality exercises are of great importance. Exercises should thoroughly be analyzed regarding their effectiveness, while user preferences and expectations should be considered when designing virtual reality exercises for everyday clinical motor rehabilitation.

Corticospinal Control of a Challenging Ankle Task in Incomplete Spinal Cord Injury.

After incomplete spinal cord injury (iSCI), the control of lower extremity movements may be affected by impairments in descending corticospinal tract function. Previous iSCI studies demonstrated relatively well-preserved movement control during simple alternating dorsiflections and plantar flexions albeit with severely reduced motor strength and range of motion. This task, however, required comparably limited fine motor control, impeding the sensitivity to assess the modulatory capacity of corticospinal control. Therefore, we introduced a more challenging ankle motor task necessitating complex and dynamic feedback-based movement adjustments to modulate corticospinal drive. Nineteen individuals with iSCI and 22 control subjects performed two different ankle movement tasks: (1) a regular, auditory-guided ankle movement task at a constant frequency as baseline assessment and (2) an irregular, visually guided ankle movement task following a pre-defined trajectory as a more challenging motor task. Both tasks were performed separately and in a randomized order. Electromyography (EMG) and kinematic data were recorded. The EMG frequency characteristics were investigated using wavelet transformations. Control participants exhibited a shift of relative EMG intensity from higher (>100 Hz) to lower frequencies (20-60 Hz) comparing the regular with the irregular movement task. There is evidence that EMG activity within these lower frequencies comprise information on corticospinal drive. The EMG frequency shift was less pronounced for the less impaired leg and absent for the more impaired leg of individuals with iSCI. The precision error during the irregular task was significantly higher for individuals with iSCI (more impaired leg: 12.34 ± 11.14%; less impaired leg: 6.93 ± 2.74%) compared with control participants (4.10 ± 0.84%). These results, along with the walking performance, correlated well with the delta frequency shift between the regular and irregular movement task in the 38 Hz band (corticospinal drive frequency) in the iSCI group, suggesting that task performance is related to the capacity to modulate corticospinal control. The irregular movement task holds promise as a tool for revealing further insights into corticospinal control of single-joint movements. It may serve as a surrogate marker for the assessment of modulatory capacity and the integrity of corticospinal control in individuals with iSCI early after injury and throughout rehabilitation.

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.