Lea Awai

Visual contribution to postural stability: Interaction between target fixation or tracking and static or dynamic large-field stimulus

Stationary visual information has a stabilizing effect on posture, whereas moving visual information is destabilizing. We compared the influence of a stationary or moving fixation point to the influence of stationary or moving large-field stimulation, as well as the interaction between a fixation point and a large-field stimulus. We recorded body sway in 20 healthy subjects who were fixating a stationary or oscillating dot (vertical or horizontal motion, 1/3 Hz, +/-12 degrees amplitude, distance 96 cm). In addition, a large-field random dot pattern (extension: approximately 80 x 70 degrees) was stationary, moving or absent. Visual fixation of a stationary dot in darkness did not reduce antero-posterior (AP) sway compared to the situation in total darkness, but slightly reduced lateral sway at frequencies below 0.5 Hz. In contrast, fixating a stationary dot on a stationary large-field pattern reduced both AP and lateral body sway at all frequencies (0.1-2 Hz). Ocular tracking of the oscillating dot caused a peak in body sway at 1/3 Hz, i.e. the stimulus frequency, but there was no influence of large-field stimulus at this frequency. A stationary large-field pattern, however, reduced AP and lateral sway at frequencies between 0.1 and 2 Hz when subjects tracked a moving dot, compared to tracking in darkness. Our results demonstrate that a stationary large-field pattern has a stabilizing effect in all conditions, independent of whether the eyes are fixing on a stationary target or tracking a moving target.

Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates

Fundamental differences in the anatomy and function of the corticospinal tract support enhanced recovery of leg and hand function after lateralized spinal cord injury in primates compared to rodents, emphasizing the importance of primate models for spinal cord repair therapies. Species-specific recovery Despite decades of research and success in rodent models, there are no therapies that repair the human spinal cord. Friedli et al. looked at the reorganization and function of the corticospinal tract after spinal cord injury (SCI) in rats, monkeys, and humans. In humans with lateralized SCI (affecting only one side of the spinal cord), there was greater recovery in motor function than those with more symmetric injuries; this recovery was mirrored in monkeys with a similar SCI, but not in rats. The authors looked into why such a species divergence exists, and revealed that monkeys had a greater number of bilateral axonal projections that sprouted into denervated spinal segments below the injury, whereas rats had interrupted projections and near-complete depletion of corticospinal fibers. Thus, monkeys and humans have the potential for synaptic reorganization above and below the lesion, and this corticospinal tract reorganization correlates with functional recovery. The authors suggest that primate models should be considered more frequently for research aimed at SCI repair and therapeutics, but acknowledge the importance of rodent models in the field. Furthermore, because the degree of laterality correlates with a positive outcome, the authors suggest that it be factored into clinical trial design. 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 have 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 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 did 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 interspecies 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 reemphasizes the importance of primate models for designing clinically relevant treatments.

Intralimb coordination as a sensitive indicator of motor-control impairment after spinal cord injury.

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.

Influence of Spinal Cord Integrity on Gait Control in Human Spinal Cord Injury.

Background. Clinical trials in spinal cord injury (SCI) primarily rely on simplified outcome metrics (ie, speed, distance) to obtain a global surrogate for the complex alterations of gait control. However, these assessments lack sufficient sensitivity to identify specific patterns of underlying impairment and to target more specific treatment interventions. Objective. To disentangle the differential control of gait patterns following SCI beyond measures of time and distance. Methods. The gait of 22 individuals with motor-incomplete SCI and 21 healthy controls was assessed using a high-resolution 3-dimensional motion tracking system and complemented by clinical and electrophysiological evaluations applying unbiased multivariate analysis. Results. Motor-incomplete SCI patients showed varying degrees of spinal cord integrity (spinal conductivity) with severe limitations in walking speed and altered gait patterns. Principal component (PC) analysis applied on all the collected data uncovered robust coherence between parameters related to walking speed, distortion of intralimb coordination, and spinal cord integrity, explaining 45% of outcome variance (PC 1). Distinct from the first PC, the modulation of gait-cycle variables (step length, gait-cycle phases, cadence; PC 2) remained normal with respect to regained walking speed, whereas hip and knee ranges of motion were distinctly altered with respect to walking speed (PC 3). Conclusions. In motor-incomplete SCI, distinct clusters of discretely controlled gait parameters can be discerned that refine the evaluation of gait impairment beyond outcomes of walking speed and distance. These findings are specifically different from that in other neurological disorders (stroke, Parkinson) and are more discrete at targeting and disentangling the complex effects of interventions to improve walking outcome following motor-incomplete SCI.

Rehabilitation-Dependent Neural Plasticity After Spinal Cord Injury

Complex movements are programmed in the central nervous system (CNS) and adapted by proprioceptive feedback. The selection of and interaction between different sources of afferent input is task dependent. Simple stretch reflexes are thought to be involved primarily in the control of focal movement. For more complex motor behaviors such as locomotion, afferent input related to load and hip-joint position probably has an important role in the proprioceptive contribution to the activation pattern of the leg muscles. Advances in our understanding of movement control allow us to define more precisely the requirements for the rehabilitation of patients with movement disorders. Accordingly, acknowledging the discrepancy between spasticity as assessed by clinical bedside testing and spasticity as presented in movement disorders affecting gait is essential to appreciate the true impact of spasticity. Central motor lesions are associated with a loss of supraspinal drive and defective use of afferent input. These changes lead to paresis and maladaptation of the movement pattern. Secondary changes in mechanical muscle fiber and collagen tissue result in spastic muscle tone, which in part compensates for paresis and allows functional movements on a simpler level of organization. The respective contributions to an aberrant gait pattern are complex and the resolution benefits from applying detailed kinematic movement analyses complementary to clinical measures to reveal changes in motor control. The distinct capacity of subjects with an incomplete spinal cord injury (iSCI) to remain able to modulate time–distance parameters but revealing complex impairments of intralimb coordination and the dissimilar responsiveness to rehabilitative interventions reveal distinct domains of neural control of walking. More sensitive outcome measures will be essential to uncover the respective contributions of restitution (i.e., repair of damaged neural structures) and mechanisms attributable to adaptation and compensatory movement strategies to rehabilitation-dependent functional improvements.

Comprehensive assessment of walking function after human spinal cord injury

Regaining any locomotor function after spinal cord injury is not only of immediate importance for affected patients but also for clinical research as it allows to investigate mechanisms underlying motor impairment and locomotor recovery. Clinical scores inform on functional outcomes that are clinically meaningful to value effects of therapy while they all lack the ability to explain underlying mechanisms of recovery. For this purpose, more elaborate recordings of walking kinematics combined with assessments of spinal cord conductivity and muscle activation patterns are required. A comprehensive assessment framework comprising of multiple complementary modalities is necessary. This will not only allow for capturing even subtle changes induced by interventions that are likely missed by standard clinical outcome measures. It will be fundamental to attribute observed changes to naturally occurring spontaneous recovery in contrast to specific changes induced by novel therapeutic interventions beyond the improvements achieved by conventional therapy.

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

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.