Laurent J. Bouyer

Pharmacological Activation and Modulation of the Central Pattern Generator for Locomotion in the Cata

Abstract: Pharmacological agents have been shown to be capable of inducing a pattern of rhythmic activity recorded in muscle nerves or motoneurons of paralyzed spinal cats that closely resembles the locomotor pattern seen in intact cats. Further work, using intraperitoneal or intrathecal injections, suggests that different neurotransmitters may be involved in various aspects of locomotor control, e.g., initiation and modulation of the pattern. Although precursors, agonists or the neurotransmitters themselves of several systems have been investigated (noradrenergic, dopaminergic, serotonergic, glutamatergic), the noradrenergic system seems the most efficient in triggering locomotion in complete spinal cats, with the α‐2 agonists (clonidine, tizanidine, oxymetazoline) being more potent than the α‐1 agonist, methoxamine. Moreover, the potency of the drugs may depend on the time of application after the spinal lesion. In chronic spinal cats capable of spontaneous walking on hindlimbs on the treadmill, all neurotransmitters appear to exert distinct recognizable effects on the locomotor pattern. More recent work also suggests that the effects of drugs may differ significantly depending on the type of spinal lesion. For instance, clonidine further reduces the level of weight support during quadrupedal locomotion of cats with lesions of the ventral‐ventrolateral funiculi, possibly due to an interference of clonidine with essential compensatory mechanisms used by these animals to walk. Such considerations as the type of drugs, type of lesions, and the time after the lesion will be important for future studies in spinal cord injured patients.

Recovery of locomotion in the cat following spinal cord lesions.

In most species, locomotor function beneath the level of a spinal cord lesion can be restored even if the cord is completely transected. This suggests that there is, within the spinal cord, an autonomous network of neurons capable of generating a locomotor pattern independently of supraspinal inputs. Recent studies suggest that several physiological and neurochemical changes have to occur in the neuronal networks located caudally to the lesion to allow the expression of spinal locomotion. Some evidence of this plasticity will be addressed in this review. In addition, original data on the functional organisation of the lumbar spinal cord will also be presented. Recent works in our lab show that segmental responsiveness of the spinal cord of the cat to locally micro-injected drugs in different lumbar segments, in combination with complete lesions at various level of the spinal cord, suggest a rostro-caudal organisation of spinal locomotor control. Moreover, the integrity of midlumbar segments seems to be crucial for the expression of spinal locomotion. These data suggest that the regions of critical importance for locomotion can be confined to a restricted portion of the spinal cord. Later, these midlumbar segments could be targeted by electrical stimulation or grafts to improve recovery of function. Understanding the changes in spinal cord neurophysiology and neurochemistry after a lesion is of critical importance to the improvement of treatments for locomotor rehabilitation in spinal-cord-injured patients.

Involvement of the corticospinal tract in the control of human gait.

Given the inherent mechanical complexity of human bipedal locomotion, and that complete spinal cord lesions in human leads to paralysis with no recovery of gait, it is often suggested that the corticospinal tract (CST) has a more predominant role in the control of walking in humans than in other animals. However, what do we actually know about the contribution of the CST to the control of gait? This chapter will provide an overview of this topic based on the premise that a better understanding of the role of the CST in gait will be essential for the design of evidence-based approaches to rehabilitation therapy, which will enhance gait ability and recovery in patients with lesions to the central nervous system (CNS). We review evidence for the involvement of the primary motor cortex and the CST during normal and perturbed walking and during gait adaptation. We will also discuss knowledge on the CST that has been gained from studies involving CNS lesions, with a particular focus on recent data acquired in people with spinal cord injury.

Timing-Specific Transfer of Adapted Muscle Activity After Walking in an Elastic Force Field

Human locomotion results from interactions between feedforward (central commands from voluntary and automatic drive) and feedback (peripheral commands from sensory inputs) mechanisms. Recent studies have shown that locomotion can be adapted when an external force is applied to the lower limb. To better understand the neural control of this adaptation, the present study investigated gait modifications resulting from exposure to a position-dependent force field. Ten subjects walked on a treadmill before, during, and after exposure to a force field generated by elastic tubing that pulled the foot forward and up during swing. Lower limb kinematics and electromyographic (EMG) activity were recorded during each walking period. During force field exposure, peak foot velocity was initially increased by 38%. As subjects adapted, peak foot velocity gradually returned to baseline in <or=125 strides. In the adapted state, hamstring EMG activity started earlier (16% before toe off) and remained elevated throughout swing. After force field exposure, foot velocity was initially reduced by 22% and returned to baseline in 9-51 strides. Aftereffects in hamstring EMGs consisted of increased activity around toe off. Contrary to the adapted state, this increase was not maintained during the rest of swing. Together, these results suggest that while the neural control of human locomotion can adapt to force field exposure, the mechanisms underlying this adaptation may vary according to the timing in the gait cycle. Adapted hamstring EMG activity may rely more on feedforward mechanisms around toe off and more on feedback mechanisms during the rest of swing.

An ElectroHydraulic Actuated Ankle Foot Orthosis to Generate Force Fields and to Test Proprioceptive Reflexes During Human Walking

The control of human walking can be temporarily modified by applying forces to the leg. To study the neural mechanisms underlying this adaptive capacity, a device delivering controlled forces and high-velocity displacements to the ankle was designed. A new solution, involving a closed circuit hydraulic system composed of two cylinders (master-slave) mutually connected by hoses and controlled by an electric motor was preferred over classical mechanical/electrical approaches. The slave cylinder delivers desired torques to the ankle using a light weight, custom-designed ankle-foot orthosis. This electrohydraulic orthosis (EHO) can produce several types of force fields during walking, including constant, position-dependent, and phase-dependent. With phase-dependent force fields, active torque cancellation maintains low-residual torques (les1.85 Nm root mean square) outside of the zone of force application for walking speeds ranging from 0.2 to 4.5 km/h. Rapid ankle stretches/unloads (>200deg/s) can also be produced alone or during force field application, and elicited proprioceptive reflexes in ankle muscles. In conclusion, the EHO is capable of delivering controlled force fields and of activating proprioceptive reflexes during human walking. It will provide the flexibility needed to test the adaptability of healthy and pathological gait control, and to address some of its underlying neural mechanisms.

Determinants of locomotor recovery after spinal injury in the cat

After a spinalization at the most caudal thoracic spinal segment, the cat can recover locomotion of the hindlimbs when they are placed on a moving treadmill. This chapter summarizes some of the determinants of such a dramatic recovery of motor function. Fundamental to this recovery is undoubtedly the genetically based spinal locomotor generator, which provides an essential rhythmicity to spinal motoneurons and hence the musculature. Other factors are also important, however. Sensory feedback is essential for the correct expression of spinal locomotion because spinal cats, devoid of cutaneous feedback from the hindfeet, are incapable of plantar foot placement. The neurochemical environment also adapts to spinalization, i.e., the loss of all modulation by descending monoaminergic pathways. Post-transection spinal rhythmicity then becomes more dependent on glutamatergic mechanisms. Finally, we argue that the mid-lumbar spinal segments evolve to play a crucial role in the elaboration of spinal locomotion as their inactivation abolishes spinal locomotion. In summary, the above findings suggest that the recovery of spinal locomotion is determined by a number of factors, each of which must now be more fully understood in the ever-continuing effort to improve the rehabilitation of spinal-cord-injured subjects.

The Spinal Cat

A number of reviews have summarized important insights on the role played by various nervous system structures in the control of locomotion (1–8). These reviews have also highlighted the remarkable locomotor capacities of the spinal cord after a complete spinal transection, which removes all the ascending and descending pathways normally exerting important control over spinal cord functions. The purpose of this chapter is to focus specifically on the locomotor capabilities of the spinal cat, not so much to show that “spinal” locomotion resembles “normal” locomotion but rather to illustrate the extent to which the spinal cord can express and adapt its locomotor functions in the absence of these regulatory mechanisms. Does this spinal behavior represent the contribution of the spinal cord to normal locomotion? Probably not, because in all pathologic conditions, the central nervous system utilizes whatever circuitry is available to optimize its functions. It is possible that some mechanisms are less important in the normal cat but become essential for locomotion after spinalization, such as some sensory afferents. Thus, a better understanding of the “physiopathology” of locomotion after spinal cord injury in animal models is important both in highlighting some of the principles that may help understand normal locomotion and in increasing our understanding of some of the mechanisms of recovery of a motor function following a spinal trauma. Such knowledge is important for improving the design of various types of therapeutic approaches in spinal-cord-injured patients (9,10).

Chapter 12 The cat model of spinal injury

Publisher Summary This chapter discusses the changes occurring in the spinal cord that may lead to the re-expression of motor patterns such as hind-limb locomotion. The chapter reviews some aspects of locomotor training with and without the use of drugs, the evolution of pharmacological receptors below the level of lesion. It also discusses the role of various neurotransmitter systems before and after spinalization, the key role played by certain rostral lumbar segments of the spinal cord in the generation of locomotion, and the necessity of cutaneous inputs from the pads for the expression of spinal locomotion. The chapter discusses the recovery of locomotion in adult spinal cats is probably the result of numerous plastic changes occurring at the level of the sensory afferents, cellular properties of neurons and receptors for neurotransmitters. The spinal cord is a complex laminar and segmental structure.

Tonic Pain Experienced during Locomotor Training Impairs Retention Despite Normal Performance during Acquisition

Many patients are in pain when they receive gait training during rehabilitation. Based on animal studies, it has been proposed that central sensitization associated to nociception (maladaptive plasticity) and plasticity related to the sensorimotor learning (adaptive plasticity) share similar neural mechanisms and compete with each other. The aim of this study was to evaluate whether experimental tonic pain influences motor learning (acquisition and next-day retention) of a new locomotor task. Thirty healthy human subjects performed a locomotor adaptation task (perturbing force field applied to the ankle during swing using a robotized orthosis) on 2 consecutive days. Learning was assessed using kinematic measures (peak and mean absolute plantarflexion errors) and electromyographic (EMG) activity. Half of the participants performed the locomotor adaptation task with pain on Day 1 (capsaicin cream around the ankle), while the task was performed pain-free for all subjects on Day 2 to assess retention. Pain had no significant effect on baseline gait parameters nor on performance during the locomotor adaptation task (for either kinematic or EMG measures) on Day 1. Despite this apparently normal motor acquisition, pain-free Day 2 performance was markedly and significantly impaired in the Pain group, indicating that pain during training had an impact on the retention of motor memories (interfering with consolidation and/or retrieval). These results suggest that the same motor rehabilitation intervention could be less effective if administered in the presence of pain.

Physiology of walking in patients with moderate to severe chronic obstructive pulmonary disease.

PURPOSE Little is known about the physiology of walking in chronic obstructive pulmonary disease (COPD). Our objective was to evaluate the cardiac and respiratory responses as well as the electrical activity of lower limb muscles during walking in patients with COPD compared with healthy controls. METHODS Cardiorespiratory parameters were monitored during a 6-min walking test (6 MWT) in 10 patients with COPD and 11 healthy controls. Surface EMG (sEMG) data were recorded in five muscle groups (soleus, medial gastrocnemius, tibialis anterior, vastus lateralis, and rectus femoris) of the right leg during walking. The integrated signal (iEMG) and the median frequency were obtained from the sEMG signal of each muscle group. RESULTS Although the walking distance and speed were significantly reduced in patients with COPD compared with those in controls, patients walked at a higher percentage of peak VO2. The overall sEMG patterns were similar between patients with COPD and controls. A fall in the sEMG median frequency during the 6 MWT was observed for the vastus lateralis and the rectus femoris in patients with COPD and in controls suggesting a muscle fatiguing contracting profile. CONCLUSION The 6 MWT was performed at a relatively higher intensity in patients with COPD compared with healthy controls. The progressive fall in the sEMG median frequency of the vastus lateralis and rectus femoris in both groups suggested the occurrence of a muscle fatiguing profile during walking. The performance of a daily activity such as walking imposes a high physiological demand in patients with COPD.