Ray D. de Leon

Retraining the injured spinal cord.

The present review presents a series of concepts that may be useful in developing rehabilitative strategies to enhance recovery of posture and locomotion following spinal cord injury. First, the loss of supraspinal input results in a marked change in the functional efficacy of the remaining synapses and neurons of intraspinal and peripheral afferent (dorsal root ganglion) origin. Second, following a complete transection the lumbrosacral spinal cord can recover greater levels of motor performance if it has been exposed to the afferent and intraspinal activation patterns that are associated with standing and stepping. Third, the spinal cord can more readily reacquire the ability to stand and step following spinal cord transection with repetitive exposure to standing and stepping. Fourth, robotic assistive devices can be used to guide the kinematics of the limbs and thus expose the spinal cord to the new normal activity patterns associated with a particular motor task following spinal cord injury. In addition, such robotic assistive devices can provide immediate quantification of the limb kinematics. Fifth, the behavioural and physiological effects of spinal cord transection are reflected in adaptations in most, if not all, neurotransmitter systems in the lumbosacral spinal cord. Evidence is presented that both the GABAergic and glycinergic inhibitory systems are up‐regulated following complete spinal cord transection and that step training results in some aspects of these transmitter systems being down‐regulated towards control levels. These concepts and observations demonstrate that (a) the spinal cord can interpret complex afferent information and generate the appropriate motor task; and (b) motor ability can be defined to a large degree by training.

Can the mammalian lumbar spinal cord learn a motor task

Progress toward restoring locomotor function in low thoracic spinal transected cats and the application of similar techniques to patients with spinal cord injury is reviewed. Complete spinal cord transection (T12-T13) in adult cats results in an immediate loss of locomotor function in the hindlimbs. Limited locomotor function returns after several months in cats that have not received specific therapies designed to restore hindlimb stepping. Training transected cats to step on a treadmill for 30 min.d-1 and 5 d.wk-1 greatly improves their stepping ability. The most successful outcome was in cats where training began early, i.e., 1 wk after spinal transection. Cats trained to stand instead of stepping had great difficulty using the hindlimbs for locomotion. These effects were reversible over a 20-month period such that cats unable to step as a result of standing training could be trained to step and, conversely, locomotion in stepping-trained cats could be abolished by standing training. These results indicate that the spinal cord is capable of learning specific motor tasks. It has not been possible to elicit locomotion in patients with clinically complete spinal injuries, but appropriately coordinated EMG activity has been demonstrated in musculature of the legs during assisted locomotion on a treadmill.

Tools for understanding and optimizing robotic gait training

This article reviews several tools we have developed to improve the understanding of locomotor training following spinal cord injury (SCI), with a view toward implementing locomotor training with robotic devices. We have developed (1) a small-scale robotic device that allows testing of locomotor training techniques in rodent models, (2) an instrumentation system that measures the forces and motions used by experienced human therapists as they manually assist leg movement during locomotor training, (3) a powerful, lightweight leg robot that allows investigation of motor adaptation during stepping in response to force-field perturbations, and (4) computational models for locomotor training. Results from the initial use of these tools suggest that an optimal gait-training robot will minimize disruptive sensory input, facilitate appropriate sensory input and gait mechanics, and intelligently grade and time its assistance. Currently, we are developing a pneumatic robot designed to meet these specifications as it assists leg and pelvic motion of people with SCI.

Hindlimb loading determines stepping quantity and quality following spinal cord transection.

We compared the bipedal hindlimb stepping ability of untrained and trained (step-trained 6 min/day) spinal rats (mid-thoracic spinal cord transection at post-natal day 5) at different levels of body weight support on a treadmill over a 40-day period, starting at 69 days of age. A robotic device provided precise levels of body weight support and recorded hindlimb movement. We assessed stepping ability using: (1) step quantity determined from the measured hindlimb movement, (2) ordinal scales of paw placement, weight-bearing, and limb flexion, and (3) the lowest level of body weight support at which stepping was maintained. Stepping quantity and quality depended strongly on the level of support provided. Stepping ability improved with time, but only at the higher levels of weight-bearing, and independently of training. Increasing limb loading by gradually decreasing body weight support altered the spatiotemporal properties of the steps, resulting in an increase in step length and stance duration and a decrease in swing and step cycle duration. The rats progressively improved their ability to support more load before collapsing from a maximum of about 42 g ( approximately 25% of body weight) at Day 1 to 73 g ( approximately 35% of body weight) at Day 40. We conclude that the level of hindlimb loading provided to a spinally transected rat strongly influences the quantity and quality of stepping. Furthermore, the relationship between stepping ability and loading conditions changes with time after spinal cord transection and is unaltered by small amounts of step training. Finally, load-bearing failure point can be a quantitative measure of locomotor recovery following spinal cord injury, especially for severely impaired animals that cannot step unassisted.

Extensor- and flexor-like modulation within motor pools of the rat hindlimb during treadmill locomotion and swimming

EMG activity was recorded from the vastus lateralis (VL, knee extensor), rectus femoris (RF, hip flexor and knee extensor), tibialis anterior (TA, ankle flexor and digit extensor) and either the lateral or medial gastrocnemius (LG, MG, knee flexors and ankle extensors) muscles of 7 adult rats during treadmill locomotion and swimming. Most flexors and extensors are activated as a single burst but each is known to be modulated differently during locomotion. For example, the extensor EMG bursts are shortened and amplitude elevated as speed increases, whereas little change occurs in the EMG duration and amplitude in flexors. The RF and VL displayed a double burst of EMG activity per cycle during treadmill locomotion and a single burst during swimming. Kinematic and EMG analyses showed that during running, one of these EMG bursts occurred primarily during swing while the other burst occurred primarily during stance. Modulation of the burst occurring during swing approximated a flexor pattern, while the second burst was modulated like a typical extensor when running over a range of speeds and grades on a treadmill. These data suggest that motoneurons within a motor pool of a uniarticular (VL) as well as a biarticular (RF) muscle can be modulated by more than one cyclical input, probably of central origin, and that under some conditions several motor pools may share the same central commands.

Using robotics to teach the spinal cord to walk.

We have developed a robotic device (e.g. the rat stepper) that can be used to impose programmed forces on the hindlimbs of rats during stepping. In the present paper we describe initial experiments using this robotic device to determine the feasibility of robotically assisted locomotor training in complete spinally transected adult rats. The present results show that using the robots to increase the amount of load during stance by applying a downward force on the ankle improved lift during swing. The trajectory pattern during swing was also improved when the robot arms were programmed to move the ankle in a path that approximated the normal swing trajectory. These results suggest that critical elements for successful training of hindlimb stepping in spinal cord injured rats can be implemented rigorously and evaluated using the rat stepper.

Treadmill training enhances the recovery of normal stepping patterns in spinal cord contused rats.

Treadmill training is known to improve stepping in complete spinal cord injured animals. Few studies have examined whether treadmill training also enhances locomotor recovery in animals following incomplete spinal cord injuries. In the present study, we compared locomotor recovery in trained and untrained rats that received a severe mid-thoracic contusion of the spinal cord. A robotic device was used to train and to test bipedal hindlimb stepping on a treadmill. Training was imposed for 8 weeks. The robotic device supported the weight of the rats and recorded ankle movements in the hindlimbs for movement analyses. Both the trained and untrained rats generated partial weight bearing hindlimb steps after the spinal cord contusion. Dragging during swing was more prevalent in the untrained rats than the trained rats. In addition, only the trained rats performed step cycle trajectories that were similar to normal step cycle trajectories in terms of the trajectory shape and movement velocity characteristics. In contrast, untrained rats executed step cycles that consisted of fast, kick-like movements during forward swing. These findings indicate that spinal cord contused rats can generate partial weight bearing stepping in the absence of treadmill training. The findings also suggest that the effect of treadmill training is to restore normal patterns of hindlimb movements following severe incomplete spinal cord injury in rats.

Chapter 11 Use of robotics in assessing the adaptive capacity of the rat lumbar spinal cord

We have developed a robotic device that can record the trajectory of the hindlimb movements in rats. The robotic device can also impose programmed forces on the limbs during stepping. In the present paper we describe experiments using this robotic device, i.e. the rat stepper, to determine whether step training improves the locomotor capacity of adult rats that received complete spinal cord transections as neonates. We also determined to what extent the locomotor patterns can be maintained when the step cycle is physically perturbed by the robotic device. The results of the present study demonstrate that a robotic device can be used effectively to quantify the improvements in the locomotor capacity of spinal transected rats that occurs over a period of step training. The present results also demonstrate that when an external force is imposed to disrupt the step cycle, the spinal cord has the neural control elements necessary to normalize the kinematics over a number of steps, in the face of the disrupted forces.

A Physiological Basis for the Development of Rehabilitative Strategies for Spinally Injured Patients

After a decade of studies using animal models, there is sufficient information to encourage a reassessment of the potential for recovery of motor function following spinal cord injury in humans. This review focuses on the response of the lumbosacral motor system following spinal cord injury and the effects of rehabilitative strategies such as weight support, loading, and administration of specific pharmacological agonists and antagonists on the maintenance and/or recovery of motor function. Based on clinical experience and review of related studies, the authors suggest a list of eight strategies for the improvement of rehabilitative protocols.

Changes in GABAA receptor subunit gamma 2 in extensor and flexor motoneurons and astrocytes after spinal cord transection and motor training

GABA signaling plays an important role in the spinal cord response to injury and subsequent motor training. Since benzodiazepines are commonly used to treat muscle spasticity in spinal cord injured subjects and the gamma2 subunit of the GABA(A) receptor is necessary for benzodiazepine binding, this subunit may be an important factor modulating sensorimotor function after an injury. Changes in gamma2 levels in muscle-specific motoneurons and surrounding astrocytes were determined approximately 3 months after a complete mid-thoracic spinal cord transection at P5 in non-trained and in step-trained spinal rats. Soleus (ankle extensor) and tibialis anterior (TA, ankle flexor) motor pools were identified using retrograde labeling via intramuscular injections of Fast Blue or Fluoro Gold, respectively. Lumbar spinal cord sections showed gamma2 immunostaining in both soleus and TA motoneurons and astrocytes. gamma2 immunoreactivity on the soma of soleus and TA motoneurons in spinal rats was differentially modulated. Compared to intact rats, spinal rats had higher levels of gamma2 in TA, and lower levels in soleus motoneurons. Step training restored GABA(A) gamma2 levels towards control values in motoneuronal pools of both muscles. In contrast, the gamma2 levels were elevated in surrounding astrocytes of both motor pools in spinal rats, and step training had no further effect. Thus, motor training had a specific effect on those neurons that were directly involved with the motor task. Since the gamma2 subunit is involved with GABA(A) receptor trafficking and synaptic clustering, it appears that this subunit could be an important component of the activity-dependent response of the spinal cord after a spinal injury.