Nadia Dominici

Restoring Voluntary Control of Locomotion after Paralyzing Spinal Cord Injury

Regaining Limb Movement Despite many years of intensive research, there is still an urgent need for novel treatments to help patients restore motor function after spinal cord injuries. van den Brand et al. (p. 1182) produced left and right hemisections at different levels of the rat thoracic spinal cord to cause complete hind limb paralysis mimicking the situation in humans with spinal cord injury. Systemic application of pharmacological agents, combined with a multisystem rehabilitation program including a robotic postural neuroprosthesis, restored voluntary movements of both hind limbs. A rehabilitation program involving robotic neuroprosthetics restores previously paralyzed hindlimb function. Half of human spinal cord injuries lead to chronic paralysis. Here, we introduce an electrochemical neuroprosthesis and a robotic postural interface designed to encourage supraspinally mediated movements in rats with paralyzing lesions. Despite the interruption of direct supraspinal pathways, the cortex regained the capacity to transform contextual information into task-specific commands to execute refined locomotion. This recovery relied on the extensive remodeling of cortical projections, including the formation of brainstem and intraspinal relays that restored qualitative control over electrochemically enabled lumbosacral circuitries. Automated treadmill-restricted training, which did not engage cortical neurons, failed to promote translesional plasticity and recovery. By encouraging active participation under functional states, our training paradigm triggered a cortex-dependent recovery that may improve function after similar injuries in humans.

Locomotor Primitives in Newborn Babies and Their Development

Mammalian locomotion patterns share common roots. How rudimentary movements evolve into sophisticated ones during development remains unclear. It is often assumed that the primitive patterns of neural control are suppressed during development, replaced by entirely new patterns. Here we identified the basic patterns of lumbosacral motoneuron activity from multimuscle recordings in stepping neonates, toddlers, preschoolers, and adults. Surprisingly, we found that the two basic patterns of stepping neonates are retained through development, augmented by two new patterns first revealed in toddlers. Markedly similar patterns were observed also in the rat, cat, macaque, and guineafowl, consistent with the hypothesis that, despite substantial phylogenetic distances and morphological differences, locomotion in several animal species is built starting from common primitives, perhaps related to a common ancestral neural network.

Coordination of Locomotion with Voluntary Movements in Humans

Muscle activity occurring during human locomotion can be accounted for by five basic temporal activation patterns in a variety of locomotion conditions. Here, we examined how these activation patterns interact with muscle activity required for a voluntary movement. Subjects produced a voluntary movement during locomotion, and we examined the resulting kinematics, kinetics, and EMG activity in 16-31 ipsilateral limb and trunk muscles during the tasks. There were four voluntary tasks added to overground walking (∼5 km/h) in which subjects kicked a ball, stepped over an obstacle, or reached down and grasped an object on the floor (weight support on either the right or the left foot). Statistical analyses of EMG waveforms showed that the five basic locomotion patterns were invariantly present in each task, although they could be differently weighted across muscles, suggesting a characteristic locomotion timing of muscle activations. We also observed a separate activation that was timed to the voluntary task. The coordination of locomotion with the voluntary task was accomplished by combining activation timings that were associated separately with the voluntary task and locomotion. Activation associated with the voluntary tasks was either synchronous with the timing for locomotion or had additional activations not represented in the basic locomotion timing. We propose that this superposition of an invariant locomotion timing pattern with a voluntary activation timing may be consistent with the proposal suggesting that compound movements are produced through a superposition of motor programs.

Modular Control of Limb Movements during Human Locomotion

The idea that the CNS may control complex interactions by modular decomposition has received considerable attention. We explored this idea for human locomotion by examining limb kinematics. The coordination of limb segments during human locomotion has been shown to follow a planar law for walking at different speeds, directions, and levels of body unloading. We compared the coordination for different gaits. Eight subjects were asked to walk and run on a treadmill at different speeds or to walk, run, and hop over ground at a preferred speed. To explore various constraints on limb movements, we also recorded stepping over an obstacle, walking with the knees flexed, and air-stepping with body weight support. We found little difference among covariance planes that depended on speed, but there were differences that depended on gait. In each case, we could fit the planar trajectories with a weighted sum of the limb length and orientation trajectories. This suggested that limb length and orientation might provide independent predictors of limb coordination. We tested this further by having the subjects step, run, and hop in place, thereby varying only limb length and maintaining limb orientation fixed, and also by marching with knees locked to maintain limb length constant while varying orientation. The results were consistent with a modular control of limb kinematics where limb movements result from a superposition of separate length- and orientation-related angular covariance. The hypothesis finds support in the animal findings that limb proprioception may also be encoded in terms of these global limb parameters.

Kinematics in Newly Walking Toddlers Does Not Depend Upon Postural Stability

When a toddler starts to walk without support, gait kinematics and electromyographic (EMG) activity differ from those of older children and the body displays considerable oscillations due to poor equilibrium. Postural instability clearly affects motor patterns in adults, but does instability explain why toddlers walk with a different gait? Here we addressed this question by comparing kinematics and EMGs in toddlers performing their first independent steps with or without hand or trunk support. Hand support significantly improved postural stability and some general gait parameters, reducing percent of falls, step width, lateral hip deviations and trunk oscillations. However, the kinematic and EMG patterns were unaffected by increased postural stability. In particular, the co-variance of the angular motion of the lower limb segments, the pattern of bilateral coordination of the vertical movement of the two hip joints, high variability of the foot path, the elliptic or single peak trajectory of the foot in the swing phase, and characteristic EMG bursts at foot contact remained idiosyncratic of toddler locomotion. Instead the toddler pattern shared fundamental features with adult stepping in place, suggesting that toddlers implement a mixed locomotor strategy, combining forward progression with elements of stepping in place. Furthermore, gait kinematics remained basically unchanged until the occurrence of the first unsupported steps and rapidly matured thereafter. We conclude that idiosyncratic features in newly walking toddlers do not simply result from undeveloped balance control but may represent an innate kinematic template of stepping.

Motor Patterns During Walking on a Slippery Walkway

Friction and gravity represent two basic physical constraints of terrestrial locomotion that affect both motor patterns and the biomechanics of bipedal gait. To provide insights into the spatiotemporal organization of the motor output in connection with ground contact forces, we studied adaptation of human gait to steady low-friction conditions. Subjects walked along a slippery walkway (7 m long; friction coefficient approximately 0.06) or a normal, nonslippery floor at a natural speed. We recorded gait kinematics, ground reaction forces, and bilateral electromyographic (EMG) activity of 16 leg and trunk muscles and we mapped the recorded EMG patterns onto the spinal cord in approximate rostrocaudal locations of the motoneuron (MN) pools to characterize the spatiotemporal organization of the motor output. The results revealed several idiosyncratic features of walking on the slippery surface. The step length, cycle duration, and horizontal shear forces were significantly smaller, the head orientation tended to be stabilized in space, whereas arm movements, trunk rotations, and lateral trunk inclinations considerably increased and foot motion and gait kinematics resembled those of a nonplantigrade gait. Furthermore, walking on the slippery surface required stabilization of the hip and of the center-of-body mass in the frontal plane, which significantly improved with practice. Motor patterns were characterized by an enhanced (roughly twofold) level of MN activity, substantial decoupling of anatomical synergists, and the absence of systematic displacements of the center of MN activity in the lumbosacral enlargement. Overall, the results show that when subjects are confronted with unsteady surface conditions, like the slippery floor, they adopt a gait mode that tends to keep the COM centered over the supporting limbs and to increase limb stiffness. We suggest that this behavior may represent a distinct gait mode that is particularly suited to uncertain surface conditions in general.

Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders

Central nervous system (CNS) disorders distinctly impair locomotor pattern generation and balance, but technical limitations prevent independent assessment and rehabilitation of these subfunctions. Here we introduce a versatile robotic interface to evaluate, enable and train pattern generation and balance independently during natural walking behaviors in rats. In evaluation mode, the robotic interface affords detailed assessments of pattern generation and dynamic equilibrium after spinal cord injury (SCI) and stroke. In enabling mode, the robot acts as a propulsive or postural neuroprosthesis that instantly promotes unexpected locomotor capacities including overground walking after complete SCI, stair climbing following partial SCI and precise paw placement shortly after stroke. In training mode, robot-enabled rehabilitation, epidural electrical stimulation and monoamine agonists reestablish weight-supported locomotion, coordinated steering and balance in rats with a paralyzing SCI. This new robotic technology and associated concepts have broad implications for both assessing and restoring motor functions after CNS disorders, both in animals and in humans.

Development of pendulum mechanism and kinematic coordination from the first unsupported steps in toddlers

SUMMARY The inverted pendulum model in which the centre of mass of the body vaults over the stance leg in an arc represents a basic mechanism of bipedal walking. Is the pendulum mechanism innate, or is it learnt through walking experience? We studied eight toddlers (about 1 year old) at their first unsupported steps, 18 older children (1.3–13 years old), and ten adults. Two infants were also tested repeatedly over a period of 4 months before the onset of independent walking. Pendulum mechanism was quantified from the kinematics of the greater trochanter, correlation between kinetic and gravitational potential energy of the centre of body mass obtained from the force plate recordings, and percentage of recovery of mechanical energy. In toddlers, these parameters deviated significantly (P<10–5) from those of older children and adults, indicating that the pendulum mechanism is not implemented at the onset of unsupported locomotion. Normalising the speed with the Froude number showed that the percentage of recovery of mechanical energy in children older than 2 years was roughly similar to that of the adults (less than 5% difference), in agreement with previous results. By contrast, the percentage of recovery in toddlers was much lower (by about 50%). Pendulum-like behaviour and fixed coupling of the angular motion of the lower limb segments rapidly co-evolved toward mature values within a few months of independent walking experience. Independent walking experience acts as a functional trigger of the developmental changes, as shown by the observation that gait parameters remained unchanged until the age of the first unsupported steps, and then rapidly matured after that age. The findings suggest that the pendulum mechanism is not an inevitable mechanical consequence of a system of linked segments, but requires active neural control and an appropriate pattern of inter-segmental coordination.

Development of independent walking in toddlers.

Surprisingly, despite millions of years of bipedal walking evolution, the gravity-related pendulum mechanism of walking does not seem to be implemented at the onset of independent walking, requiring each toddler to develop it. We discuss the precursor of the mature locomotor pattern in infants as an optimal starting point strategy for gait maturation.

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.