Experimental and clinical studies suggest that primate species exhibit greater recovery after lateralized compared to symmetrical spinal cord injuries. Although this observation has major implications for designing clinical trials and translational therapies, advantages in recovery of nonhuman primates over other species has not been shown statistically to date, nor have the associated repair mechanisms been identified. We monitored recovery in more than 400 quadriplegic patients and found that that functional gains increased with the laterality of spinal cord damage. Electrophysiological analyses suggested that corticospinal tract reorganization contributes to the greater recovery after lateralized compared with symmetrical injuries. To investigate underlying mechanisms, we modeled lateralized injuries in rats and monkeys using a lateral hemisection, and compared anatomical and functional outcomes with patients who suffered similar lesions. Standardized assessments revealed that monkeys and humans showed greater recovery of locomotion and hand function than rats. Recovery correlated with the formation of corticospinal detour circuits below the injury, which were extensive in monkeys, but nearly absent in rats. Our results uncover pronounced inter-species differences in the nature and extent of spinal cord repair mechanisms, likely resulting from fundamental differences in the anatomical and functional characteristics of the motor systems in primates versus rodents. Although rodents remain essential for advancing regenerative therapies, the unique response of the primate corticospinal tract after injury re-emphasizes the importance of primate models for designing clinically relevant treatments.

Key factors positively influencing rehabilitation and functional recovery after spinal cord injury (SCI) include training variety, intensive movement repetition, and motivating training tasks. Systems supporting these aspects may provide profound gains in rehabilitation, independent of the subject’s treatment location. In the present study, we test the hypotheses that virtual reality (VR)-augmented training at home (i.e., unsupervised) is feasible with subjects with an incomplete SCI (iSCI) and that it improves motor functions such as lower limb muscle strength, balance, and functional mobility. In the study, 12 chronic iSCI subjects used a home-based, mobile version of a lower limb VR training system. The system included motivating training scenarios and combined action observation and execution. Virtual representations of the legs and feet were controlled via movement sensors. The subjects performed home-based training over 4 weeks, with 16–20 sessions of 30–45 min each. The outcome measures assessed were the Lower Extremity Motor Score (LEMS), Berg Balance Scale (BBS), Timed Up and Go (TUG), Spinal Cord Independence Measure mobility, Walking Index for Spinal Cord Injury II, and 10 m and 6 min walking tests. Two pre-treatment assessment time points were chosen for outcome stability: 4 weeks before treatment and immediately before treatment. At post-assessment (i.e., immediately after treatment), high motivation and positive changes were reported by the subjects (adapted Patients’ Global Impression of Change). Significant improvements were shown in lower limb muscle strength (LEMS, P = 0.008), balance (BBS, P = 0.008), and functional mobility (TUG, P = 0.007). At follow-up assessment (i.e., 2–3 months after treatment), functional mobility (TUG) remained significantly improved (P = 0.005) in contrast to the other outcome measures. In summary, unsupervised exercises at home with the VR training system led to beneficial functional training effects in subjects with chronic iSCI, suggesting that it may be useful as a neurorehabilitation tool.Trial registrationCanton of Zurich ethics committee (EK-24/2009, PB_2016-00545), : NCT02149186. Registered 24 April 2014.

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Background: Recovery of walking function after neurotrauma, e.g., after spinal cord injury, is routinely captured using standardized walking outcome measures of time and distance. However, these measures do not provide information on possible underlying mechanisms of recovery, nor do they tell anything about the quality of gait. Subjects with an incomplete spinal cord injury are a very heterogeneous group of people with a wide range of functional impairments. A stratification of these subjects would allow increasing sensitivity for hypothesis testing and a more targeted treatment strategy.Methods: The gait of incomplete spinal cord injured subjects was compared to healthy control subjects by analyzing kinematic data obtained by a 3-D motion capture system. Hip–knee angle-angle plots (cyclograms) informed on the qualitative aspect of gait and the intralimb coordination. Features of the cyclogram, e.g., shape of the cyclogram, cycle-to-cycle consistency and its modulation due to changes in walking speed were discerned and used to stratify spinal cord injured subjects.Results: Spinal cord injured subjects were unable to modulate their cyclogram configuration when increasing speed from slow to preferred. Their gait quality remained clearly aberrant and showed even higher deviations from normal when walking at preferred speed. Qualitative categorization of spinal cord injured subjects based on their intralimb coordination was complemented by quantitative measures of cyclogram shape comparison.Discussion: Spinal cord injured subjects showed distinct distortions of intralimb coordination as well as limited modulation to changes in walking speed. The specific changes of the cyclograms revealed complementary insight in the disturbance of lower-limb control in addition to measures of time and distance and may be a useful tool for patient categorization and stratification prior to clinical trial inclusion.

BackgroundBody weight supported locomotor training was shown to improve walking function in neurological patients and is often performed on a treadmill. However, walking on a treadmill does not mimic natural walking for several reasons: absent self-initiation, less active retraction of leg required and altered afferent input. The superiority of overground training has been suggested in humans and was shown in rats demonstrating greater plasticity especially in descending pathways compared to treadmill training. We therefore developed a body weight support system allowing unrestricted overground walking with minimal interfering forces to train neurological patients. The present study investigated the influence of different amounts of body weight support on gait in healthy individuals.MethodsKinematic and electromyographic data of 19 healthy individuals were recorded during overground walking at different levels of body weight support (0, 10, 20, 30, 40, and 50%). Upper body inclination, lower body joint angles and multi-joint coordination as well as time-distance parameters were calculated. Continuous data were analyzed with regard to distinct changes within a gait cycle across all unloading conditions.ResultsTemporal gait parameters were most sensitive to changes in body unloading while spatial variables (step length, joint angles) showed modest responses when unloaded by as much as 50% body weight. The activation of the gastrocnemius muscle showed a gradual decrease with increasing unloading while the biceps femoris muscle showed increased activity levels at 50% unloading. These changes occurred during stance phase while swing phase activity remained unaltered.ConclusionsHealthy individuals were able to keep their walking kinematics strikingly constant even when unloaded by half of their body weight, suggesting that the weight support system permits a physiological gait pattern. However, maintaining a given walking speed using close-to-normal kinematics while being unloaded was achieved by adapting muscle activity patterns. Interestingly, the required propulsion to maintain speed was not achieved by means of increased gastrocnemius activity at push-off, but rather through elevated biceps femoris activity while retracting the leg during stance phase. It remains to be investigated to what extent neurological patients with gait disorders are able to adapt their gait pattern in response to body unloading.

Study DesignThis is a focused review article.ObjectivesTo 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.MethodsThis 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.ResultsThere 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.ConclusionThere 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.SponsorsCraig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.

Recovery of locomotor function after incomplete spinal cord injury (iSCI) is clinically assessed through walking speed and distance, while improvements in these measures might not be in line with a normalization of gait quality and are, on their own, insensitive at revealing potential mechanisms underlying recovery. The objective of this study was to relate changes of gait parameters to the recovery of walking speed while distinguishing between parameters that rather reflect speed improvements from factors contributing to overall recovery. Kinematic data of 16 iSCI subjects were repeatedly recorded during in-patient rehabilitation. The responsiveness of gait parameters to walking speed was assessed by linear regression. Principal component analysis (PCA) was applied on the multivariate data across time to identify factors that contribute to recovery after iSCI. Parameters of gait cycle and movement dynamics were both responsive and closely related to the recovery of walking speed, which increased by 96%. Multivariate analysis revealed specific gait parameters (intralimb shape normality and consistency) that, although less related to speed increments, loaded highly on principal component one (PC1) (58.6%) explaining the highest proportion of variance (i.e., recovery of outcome over time). Interestingly, measures of hip, knee, and ankle range of motion showed varying degrees of responsiveness (from very high to very low) while not contributing to gait recovery as revealed by PCA. The conjunct application of two analysis methods distinguishes gait parameters that simply reflect increased walking speed from parameters that actually contribute to gait recovery in iSCI. This distinction may be of value for the evaluation of interventions for locomotor recovery.

Although the central nervous system has a limited capacity for regeneration after acute brain and spinal cord injuries, it can reveal extensive morphological changes. Occasionally, the formation of an extensive syrinx in the spinal cord can be observed that causes no or only limited signs of functional impairment. This condition creates a unique opportunity to evaluate the mismatch between substantial morphological changes and functional outcomes. We identified seven patients with holocord syringomyelia affecting the cervical cord following chronic traumatic thoracic/lumbar spinal cord injury (19-34 years after injury) or holocord syringomyelia of non-traumatic origin, and anatomical syrinx dimensions (length, cross-sectional area) were determined using sagittal and axial magnetic resonance imaging scans. Motorand sensory-pathway integrity were evaluated using electrophysiological assessments (i.e., motor, dermatomal sensory, and dermatomal contact-heat [dCHEP] evoked potentials, as well as nerve conduction studies). These were specifically compared to clinical measures of upper-limb strength and grasping performance, including three-dimensional motion analysis. Despite extensive anatomical changes of the cervical cord (on average 26% reduction of residual spinal cord area and intrusion of almost the entire cervical spinal cord), a clinically relevant impairment of upper-limb motor function was absent while only subtle sensory deficits could be detected. dCHEPs revealed the highest sensitivity by disclosing impairments of spinothalamic pathways. Comparable to that of the brain, extensive anatomical changes of the spinal cord can occur with only subtle functional impairment. The time scale of slowly-emerging morphological alterations is essential to permit an enormous capacity for plasticity of the spinal cord. Although the central nervous system has a limited capacity for regeneration after acute brain and spinal cord injuries, it can reveal extensive morphological changes. Occasionally, the formation of an extensive syrinx in the spinal cord can be observed that causes no or only limited signs of functional impairment. This condition creates a unique opportunity to evaluate the mismatch between substantial morphological changes and functional outcomes. We identified seven patients with holocord syringomyelia affecting the cervical cord following chronic traumatic thoracic/lumbar spinal cord injury (19-34 years after injury) or holocord syringomyelia of non-traumatic origin, and anatomical syrinx dimensions (length, cross-sectional area) were determined using sagittal and axial magnetic resonance imaging scans. Motor-and sensorypathway integrity were evaluated using electrophysiological assessments (i.e., motor, dermatomal sensory, and dermatomal contact-heat [dCHEP] evoked potentials, as well as nerve conduction studies). These were specifically compared to clinical measures of upper-limb strength and grasping performance, including three-dimensional motion analysis. Despite extensive anatomical chang...