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Centre for Research in Neurological Sciences, CIHR Group in Neurological Sciences, Department of Physiology, Université de Montréal, Montreal, Canada
ABSTRACT I. GENERAL INTRODUCTION II. SENSORIMOTOR INTERACTIONS IN THE SPINAL CORD DURING LOCOMOTION A. Cutaneous Afferents 1. Removal of cutaneous inputs 2. Tonic cutaneous stimulation: triggering, inhibiting, or enhancing locomotion 3. Phasic cutaneous inputs: correcting the steps A) MECHANICAL SKIN STIMULATION IN CATS: STUMBLING CORRECTIVE REACTION. B) MECHANICAL SKIN STIMULATION IN HUMANS: TRIPPING. C) ELECTRICAL STIMULATION OF CUTANEOUS AFFERENTS IN CATS. D) ELECTRICAL STIMULATION OF CUTANEOUS AFFERENTS IN HUMANS. B. Muscle Afferents 1. Initiating and blocking the locomotor rhythm 2. Effects on timing: resetting and entrainment A) OBSERVATIONS IN ANIMALS. B) PATHWAYS INVOLVED IN RESETTING AND ENTRAINMENT IN ANIMALS. C) OBSERVATIONS IN HUMANS. 3. Role of muscle proprioceptive afferents on muscle discharge amplitude A) REMOVAL OF MUSCLE AFFERENTS. B) FUSIMOTOR DRIVE. C) LOCOMOTOR TASK-DEPENDENT MODULATION OF STRETCH REFLEX AND H-REFLEX. D) PHASE-DEPENDENT MODULATION OF STRETCH REFLEX AND H-REFLEX. E) PHASE-DEPENDENT MODULATION AND ROLE OF PROPRIOCEPTIVE PATHWAYS IN CONTROLLING MUSCLE DISCHARGE AMPLITUDE. F) PLASTICITY OF PATHWAYS FOLLOWING SPINAL INJURIES. C. Other Afferents III. SENSORIMOTOR INTERACTIONS AT SUPRASPINAL LEVELS A. Overview of the Supraspinal Control of Locomotion B. Modulation of Descending Inputs C. Dynamic Sensorimotor Interactions at the Supraspinal Level Cutaneous inputs A) ROLE OF CUTANEOUS INPUTS IN THE INITIATION OF LOCOMOTION. B) ROLE OF CUTANEOUS INPUTS IN STOPPING LOCOMOTOR BEHAVIOR. C) ROLE OF CUTANEOUS INPUTS IN THE CONTROL OF ONGOING LOCOMOTOR ACTIVITY. 2. Auditory and vibratory inputs 3. Vestibular inputs 4. Visual inputs 5. Interactions between visual and vestibular inputs IV. CELLULAR AND NETWORK MECHANISMS OF SENSORIMOTOR INTERACTIONS A. Presynaptic Inhibition 1. State- and task-dependent locomotor-related PADs 2. Phasic locomotor-related PADs 3. Sensory control of PAD pathways 4. State- and phase-dependent antidromic discharges 5. Supraspinal control of PADs B. Interneuronal Activity 1. Locomotor-related activity of spinal interneurons 2. Group I interneuron responses and recurrent inhibition during fictive locomotion 3. Group II interneurons responses and activities during fictive locomotion 4. Cervical interneurons in forelimb sensory pathways 5. Presynaptic inhibition of interneuronal axons C. Membrane Properties 1. Locomotor-drive potential 2. Plateau potentials V. CONCLUDING REMARKS GRANTS ACKNOWLEDGMENTS REFERENCES
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I. GENERAL INTRODUCTION |
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At the onset, it should be stated that removal of all or most sensory afferents by dorsal rhizotomy does not prevent the expression of rhythmic patterns such as locomotion (223–225, 255, 589). Similarly, after pyridoxine intoxication, which destroys large-diameter sensory fibers, cats do eventually recover locomotion even though the large afferents have not recovered (430). In humans, the permanent loss of large sensory fibers below the neck leads to important impairment of walking (reduced joint excursion, enlarged base of support), although slow walking, under visual guidance, is still possible (324).Other work has also clearly shown that after paralysis, induced by a chemical neuromuscular blockade, a complex and detailed rhythmic pattern can be recorded from muscle nerves ("fictive locomotion") when decerebrate and spinal cats are injected with L-DOPA (254, 433) (see also Fig. 7). These basic findings led to the proposal of the existence of a central pattern generator (CPG) for locomotion, i.e., spinal networks of neurons capable of generating a detailed rhythmic locomotor pattern in the absence of descending or afferent inputs (244).
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The expression "dynamic interactions" is taken here to include various conditions in which afferent inputs and the CPG exert a reciprocal influence so that both are changed by the activity of one another. More generally, the term dynamic refers to situations in which evoked responses change as a function of state (or task) or as a function of the phases of the task. Generally, state-dependent modulation refers to a modulation of reflex responses occurring during a "locomotor state" relative to a "resting state." Task-related modulation, on the other hand, refers to different locomotor tasks (walking, running, walking backward or forward). State- or task-dependent interactions could result in a change of response characteristics (inhibitory to excitatory or vice versa) at transition from rest to locomotion (state) or from forward to backward locomotion (task), or from standing to walking or running (tasks). For instance, an inhibitory response in one state or task may become excitatory in another state or vice versa. Responses that vary systematically as a function of the various phases or subphases of cyclical movements are referred to as phase-dependent responses. Thus an excitatory response in some muscles in one phase can be absent in the opposite phase, or become inhibitory or excitatory to another set of muscles. A less obvious type of dynamic sensorimotor interaction is observed when an afferent input is maintained tonically (for instance, a tonic flexion of a joint or a continuous pinch of the skin) or when afferent inputs are removed, as in the case of a chronic neurectomy or nerve block with a local anesthetic. In these conditions, the tonic input is the same throughout all phases of locomotion, but since locomotion continues, the tonic input dynamically interacts with each subphase of the centrally generated cycle. These dynamic interactions may also evolve with time, for instance, in cases of permanent neurectomy, in which condition sensorimotor motor interactions must undergo some plastic changes.
Mechanisms and sites of dynamic interactions are numerous, and Figure 1 points to some of the possibilities. Afferent inputs from muscles or the skin reach the spinal cord, project to motoneurons directly or through interneurons (influenced by the CPG), or through the CPG itself. Afferents also send collaterals through ascending pathways (directly or via relay interneurons) reaching supraspinal structures (telencephalon, brain stem), which in turn project down to the spinal cord on neurons that may or may not also be contacted by the same primary afferent. Through various mechanisms for selecting motor patterns (locomotion, scratching, fast paw shake), sets of membrane properties (i.e., locomotor drive potential, plateau potentials) are activated. In Figure 1, these mechanisms are only shown for motoneurons in the spinal cord and for one idealized cell in supraspinal structures. For instance, at the brain stem level of the lamprey, sensory inputs of graded strength evoke graded potentials in the reticulospinal cells leading, eventually, to a sustained plateau potential and cell discharges and to the initiation of swimming. There is thus a dynamic transformation of a sensory signal into a motor command, and this relies on intrinsic membrane properties of brain stem neurons. At the spinal cord level, sets of interneurons will be selected (interneuronal selection) to allow or block transmission during a given task or else control the transmission in a phase-dependent manner. Finally, through presynaptic inhibition that may occur at different sites (see yellow areas for selected examples), the efficacy of transmission in different tasks and phases of the task may be regulated. It is fascinating to think that probably all these regulatory mechanisms giving rise to a vast repertoire of purposeful dynamic sensorimotor interactions are at play simultaneously during locomotion.
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fibers reveals both abnormalities in gait pattern as well as a great reduction in compensatory adaptive reflexes (572). Parkinsonian patients have also been shown to have a reduced proprioception, which might account for part of their characteristic locomotor deficits (133). The plan of the review is as follows. In section II, we describe, in various animal preparations, and humans when applicable, state- and phase-dependent spinal reflexes during locomotion in response to various types of sensory inputs (cutaneous and proprioceptive) and indicate their potential contributions not only to adapt locomotion to unexpected perturbations but also to the elaboration of the normal locomotor pattern. Some pathways and mechanisms are suggested to explain certain types of sensorimotor interactions, but some of these common mechanisms are discussed in more detail in the last part of the review. In section III, we describe dynamic sensorimotor interactions between supraspinal structures, activated by sensory inputs either relayed from the spinal cord or by "special senses" pathways reaching supraspinal structures directly. These illustrate how such interactions, together with spinal interactions, lead to a system of coherent corrective responses that will be integrated with the ongoing locomotion. In section IV, a particular emphasis will be put on presynaptic, interneuronal selection, and motoneuronal mechanisms which may, in isolation or in combination, control some of the dynamic sensorimotor interactions during locomotion described in sections III and IV.
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II. SENSORIMOTOR INTERACTIONS IN THE SPINAL CORD DURING LOCOMOTION |
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The natural activation of cutaneous fibers can be assessed by recording the actual discharges of single cutaneous afferents or whole cutaneous nerves during locomotion. Only a few studies were performed on the activation of single cutaneous fibers during treadmill locomotion of intact cats (348, 351). Although most of the units discharged as predicted from the direct activation of their receptive field with the external milieu, other units fired probably as a result of movement-related skin stretches. Some of these units discharged two bursts per cycle. Recording of cutaneous nerves with chronically implanted electrodes (266) also showed whole nerve discharges in distinct phases of the cycle (449). The newly developed method to record multiple single units with electrode arrays inserted in dorsal root ganglia in walking decerebrate cats (14) should provide a wealth of new data on the discharges of cutaneous units especially in relation to proprioceptive afferent units and clarify their relative importance in signaling sensory inputs during various subphases of the locomotor cycle.
For the time being, however, the majority of the work for assessing the role of cutaneous information during locomotion was performed using neurectomies/anesthesia or mechanical stimulation of the skin or electrical stimulation of the skin or skin nerves in different parts of the step cycle.
1. Removal of cutaneous inputs
Early work of Sherrington (531) showed that removing cutaneous inputs from the hindlimbs did not prevent locomotion even after spinalization. This was largely supported by others who reported little deficits when cutting cutaneous nerves in otherwise intact cats (163) or infiltrating the central foot pad with a local anesthetic (190). Anesthesia of the dorsum of the foot in chronic spinal cat (207) or intact cat (462) does not prevent locomotion. However, unpublished observations (S. Grillner and S. Rossignol, unpublished data) showed that anesthesia of the foot pad in chronic spinal cats interfered with foot placement.
Recent work on denervation of the foot pads shed more light on the issue of the contribution of cutaneous inputs to locomotion (48–51, 481). Five cutaneous nerves innervating the hindfeet were cut and prevented from regenerating by capping their proximal end with a polymer cuff. After the denervation, cats with an intact spinal cord could walk almost normally on a treadmill (Fig. 2, A–D). Detailed electromyogram (EMG) and kinematic analyses of treadmill walking showed a long-term adaptation to the denervation consisting essentially in a faster swing (accompanied by an increase in knee and ankle flexors EMG activity), an increased foot lift, as well as a 5–10% increase in double support. The main deficit, however, occurred during precision walking when cats tried to walk on the rungs of an horizontal ladder. Early after the denervation, cats were unable to place their feet on the rungs, and this lasted for 3–7 wk. Eventually, ladder walking recovered but was never quite normal, with cats tending to grip the rungs of the ladder with a clawlike position of the paws. It is thus reasonable to think that cutaneous sensory inputs normally provide the sensory cues necessary to adjust walking, on a step by step basis, i.e., dynamically. It is very likely that the kinematic methods used in that study were not precise enough to assess the fine positioning of the foot during ordinary walking on a treadmill or over ground. Increasing the walking difficulty probably enhanced a subtle deficit undetected during level treadmill walking. Further evidence for this comes from the observation that walking on a tilted treadmill was also mildly deficient after denervation, suggesting that the cycle-to-cycle cutaneous inputs from the pads provide a regulatory input to assess load on the limbs during up- and down-going slopes. The vertical and antero-posterior (fore-aft) force distribution measured on a walkway equipped with force platforms was similar before and after denervation, whereas the medio-lateral force during stance doubled after denervation (50). This increase in medio-lateral force may represent a strategy toward a more secure walk by increasing the base of support. It could however also represent a deficit in the correct positioning of the foot secondary to the cutaneous denervation of the hindpaws.
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The transmission of cutaneous inputs was also found to be modified following locomotor training on a treadmill of spinal cats, indicating the important role of cutaneous feedback for locomotor recovery (104). The amplitude of several cutaneous responses evoked in motoneurons by three different cutaneous hindlimb nerves was significantly modified following 1 mo of locomotor training. The main effect was a decrease in cutaneous transmission excitability mainly from the medial plantar nerve (MPL) innervating the plantar surface of the foot. This reduction in cutaneous reflex sensitivity by locomotor training may somewhat offset the hyper-reflexia that tends to occur after chronic spinalization (see Ref. 571 for rats).
The experiments in spinal animals have shown the importance of cutaneous inputs for locomotion. The fact that intact cats can walk without cutaneous inputs should not be interpreted to mean that cutaneous inputs are not normally used but rather that other sensory modalities (i.e., proprioceptive) can substitute the missing cutaneous inputs, a substitution which most probably depends on supraspinal controls and cannot be achieved in the spinal state.
2. Tonic cutaneous stimulation: triggering, inhibiting, or enhancing locomotion
It has been reported in most studies on spinal locomotion (479) that tonic stimulation of the perineal region (scrotum, vulva, and base of the tail as well as inguinal fold; Ref. 531) is most effective in triggering alternate rhythmic activity of the hindlimbs in cats within the first 7–10 days after a complete spinalization at T13 or in strengthening weak movements later on when spinal cats have regained spontaneous locomotor movements. The activation of unspecific afferents from the perineal region presumably underlies some important survival function (such as escape from a predator), but the mechanisms of interactions of these perineal afferents with the CPG are not known.
In decerebrate rabbits, electrical stimulation of low-threshold skin afferents (A
and A) and C fibers from the lumbosacral back regions can increase the amplitude of bursts and frequency of the fictive locomotor rhythm (577). Tonic stimulation of the dorsum of the foot in paralyzed rabbits (575) or of sural nerve in cats (201) can also induce fictive locomotion together with pharmacological stimulation with monoamines.
Although tonic cutaneous stimuli may enhance the vigor or frequency of the locomotor rhythm, stimulation of some specific skin areas can also evoke rhythmic motor patterns other than locomotion. For instance, pinching the toes of a chronic spinal cat elicits brisk alternating movements of the limb with a strong simultaneous activation of several flexor muscles predominantly in the ipsilateral limb. A very similar pattern was observed in paralyzed preparations with the same type of stimulation (433). On the other hand, dipping the foot of a spinal cat in water generates a very brisk paw shake as does the placement of a piece of tape on the foot (28). In paralyzed spinal cat preparations, fictive paw shake can also be elicited by squirting water on the foot pads (433). Finally, stimuli placed on various body parts can generate scratching movements (551). It is thus clear that stimulation of specific areas and sensory modalities of the skin can induce locomotor movements or other movements that may be more appropriate.
Other types of tonic stimuli can inhibit completely either real or fictive locomotion. Pressing or pinching the skin of the lumbar region of rabbits (576) will instantly abolish locomotion and induce a state of "hypnotic" akinesia. The area of effective stimulus in the rabbit has to be wide (surfaces less than 0.3 cm2 are ineffective), and the best regions appear to be centered at the lumbar level (220). With well-controlled electrical stimulation (577), it was found that A
fibers innervating the dorsal skin areas (probably related to slowly adapting pressure receptors) on one side can block locomotion on both sides while larger (A and A) and smaller C fibers may on the contrary exert an excitatory effect as mentioned above. However, after removal of the skin, pressure on a spinous process can also block locomotion. It must therefore be concluded that other modalities than cutaneous inputs also have this capacity to arrest locomotion.
3. Phasic cutaneous inputs: correcting the steps
Although cutaneous inputs may have some general roles to play in locomotion such as triggering walking (perineal stimulation) or inhibiting walking (inhibitory inputs from the skin of the back), the main role of cutaneous inputs appears to be the correct positioning of the foot during normal walking or the correct adaptive limb responses to perturbations in different phases of the step cycle. This role requires a great deal of plasticity to adapt multijoint limb responses to a variety of possible perturbations according to the initial static position of the limbs or to the continuously changing limb position during locomotion.
There are several examples in the literature of the adaptability of cutaneous reflexes to initial conditions of the limbs (56, 215, 243, 250, 483, 484, 530); the same stimulus may give rise to responses in flexor muscles or extensor muscles depending on the initial posture of the limb, and this might be relevant to the dynamically changing positions of the limbs during locomotion. A stimulus on one side gives rise to a flexion response if the limb is extended and, conversely, to an extension response if the limb is flexed. Similar observations had originally been made by von Uexkull (584) on the starfish appendage. When hanging on one side, a stimulus would flip the appendage upwards; rotating the appendage by 180°, the same stimulus flipped the appendage upwards, activating the antagonist muscle. This reflex reversal was interpreted on the basis that the stretched muscle of an antagonist pair was more excitable than the other and therefore, whichever muscle was most stretched by the bend of the appendage responded to the stimulus.
Using a tonic stimulation such as a clip on the skin or a tonic electrical stimulation of an afferent nerve, Sherrington (531) noted that the ongoing stimulus after starting locomotion was alternately activating flexors and extensors, i.e., that the same stimulus was effective in exciting one group of muscle in one phase and the group of antagonists in the opposite phase. The expression reversal has been used to describe responses that are excitatory in one muscle group in one phase and excitatory to the antagonist muscles in the opposite phase. It has also been used to describe responses that are excitatory in one phase and inhibitory in the opposite phase, or vice versa. Several examples of phase-dependent reflex reversal during rhythmic activity such as locomotion have been described using either mechanical or electrical stimulation of the skin itself or electrical stimulation of specific cutaneous nerves and are detailed in the following paragraphs.
A) MECHANICAL SKIN STIMULATION IN CATS: STUMBLING CORRECTIVE REACTION. Responses to mechanical stimulation of the foot are phase dependent (swing/stance) as well as task dependent (forward/backward walking) and also site dependent (ventral/dorsal). This complex and refined reflex control is absolutely essential to generate avoidance responses appropriately tuned to the specific locomotor phases.
Early studies on the modulation of cutaneous reflexes during locomotion were first performed on chronic spinal cats (206–208). A rod equipped with a micro switch to indicate contact with the dorsum of the foot was used to mechanically obstruct the limb in different phases of the step cycle.
Similar responses were also studied in intact cats with a similar device or even only with air puffs (203). A contact on the dorsum of the foot during swing, as when hitting an obstacle, evokes a robust response of the limb characterized by a prominent knee flexion that rapidly withdraws the foot and then a flexion of the ankle and hip to step over the obstacle and place the foot in front of it (Fig. 3Ab). During this initial knee flexion, conflicting results have been obtained in ankle muscles. In some studies (462, 587), there was a short latency (10 ms) activation of the ankle flexor tibialis anterior (TA) presumably due to the muscle stretch imposed by the mechanical perturbation. This was immediately followed (at 
25 ms) by an activation of the ankle extensor gastrocnemius lateralis (GL). These specific responses were abolished by local anesthesia, but stretch-induced responses of the ankle flexor remain. It was hypothesized (462) that the early cutaneous responses prevented such stretch responses of ankle flexors that could be counterproductive by inducing an ankle flexion risking to catch the foot in the obstacle instead of avoiding it. In another study (65), a GL activation was also seen during the knee flexion while the TA which is normally active during swing was actively inhibited. Whether the ankle was locked or extended, the net result was to prevent a further ankle flexion. It is interesting that a similar mechanical stimulus applied to the dorsum of the foot during backward walking in intact cats (65) did not induce the same complex sequential pattern but rather evoked a simultaneous coactivation of the knee and ankle flexors leading to a modestly increased backward swing. When an obstructing perturbation is applied to the ventral surface of the paw during backward walking, there was an initial excitatory response in the ankle flexor and knee extensor which withdraws the foot forward in front of the obstacle followed by an increased knee flexion and eventually knee and ankle extension to place the foot on the supporting surface (65) (Fig. 3A, e and f). The pattern of muscle activation is thus here different from that of the obstructing perturbation during forward walking swing but achieves the same function of withdrawing the foot from the obstacle. Again, nonobstructive perturbation of the dorsal surface during swing in backward walking elicited more or less the same response as stimulation of the ventral surface during swing in forward walking.
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B) MECHANICAL SKIN STIMULATION IN HUMANS: TRIPPING. Similar studies using mechanical obstruction of the limb have been performed in humans. Experiments designed to reproduce conditions in which stumbling could occur were performed in subjects walking on a walkway equipped with a force platform. Two 8-cm metal strips embedded in the walkway were flipped upwards in early swing or late swing at times where the toe velocity was about equal so as to generate a similar stimulus when the foot touched the strip (189). When the foot touched the strip in early swing, there was an early response in biceps femoris (BF) of the ipsilateral leg in the swing phase followed by a later response in rectus femoris (RF) and a more variable response in TA. This altogether removed the foot from the obstacle and placed it in front of it. At the same time, short latency responses in hip, knee, and ankle extensor muscles were observed in the contralateral limb in the stance phase, producing an elevation of the whole body, which again allowed for a better clearance of the foot from the obstacle. In late swing, the perturbation was more threatening to the equilibrium and evoked a lowering strategy to shorten the swing and put the foot down as soon as possible. This strategy was achieved through either inhibition of the knee extensor or an activation of BF, which would indeed bring the foot down in that configuration of the limb. A third and rarer strategy also occurring in the late swing was termed a reaching strategy in which the subject increased or prolonged the hip flexion to increase toe clearance.
In a different study, instead of using a tripping device, an obstacle was released from a magnet on a treadmill at different times after heel strike (508). An elevating strategy was used in early swing, and a lowering strategy was used in late swing. In the first strategy, the foot was brought up by an early flexion at the ankle and at the knee caused by reflex activity in TA and BF. In the lowering strategy, the foot was rapidly put down and then overcame the obstacle in the next cycle. This was brought about by a short latency response in RF and Soleus. The strategy used in mid swing could be an elevating one or a lowering one. The exact afferent source for these responses was not clear. As will be detailed later, electrical stimulation of nerves responsible for the innervation of the same skin area caused a suppressive response of TA in late swing, whereas in the study reported here using mechanical contact, TA was excited. Therefore, other afferent inputs resulting from the abrupt contact of the foot with the obstacle may be responsible for these responses.
C) ELECTRICAL STIMULATION OF CUTANEOUS AFFERENTS IN CATS. Given the difficulty of applying mechanical stimulation to the skin in the different phases of walking, early work used electrical stimulation of the skin and also reported phase-dependent responses in spinal kittens (206, 208). The electrically evoked responses were generally very similar to those evoked by mechanical stimulation. An early work showed that trains of stimuli applied to the tibial or sural nerves (156) had profound effects on rhythm generation in decerebrate cats walking on a treadmill and even entrained the fictive locomotor rhythm (485). Indeed, stimulating large cutaneous fibers with short trains of pulses reduced the duration of flexion and induced a premature initiation of extension, i.e., resetting the rhythm whereas high-threshold fibers would rather prolong the flexor bursts. It was also shown that stimulating the pad and plantar surface during the stance phase increased both the amplitude and duration of the ongoing extensor activity, an action interpreted as helping to compensate for extra load (161). When given during the swing phase, the same stimulation prolonged the flexion or shortened the following extension. These early observations were followed by a number of more detailed studies establishing more precisely the phase-dependency modulation of such responses. Figure 4 illustrates a methodology often used to determine the phase dependency of reflex responses during locomotion. To retrieve the phasic modulation of amplitude of the reflex responses in a given muscle independently of the locomotor discharge of that muscle, the reflex responses at a fixed latency must be subtracted from the locomotor electromyographic signal occurring within the locomotor burst at the same time. It can thus be observed that the reflex responses in a given muscle may follow or not the locomotor activation profile of that muscle.
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10 ms) are seen in the knee flexor semitendinosus (St) [P1 responses (159)], and very often a second response, P2, appears (25 ms) in chronic spinal as well as in intact cats (203) (see also Fig. 4). This pattern is seen in several flexor muscles. These two reflex responses at different latencies can be modulated differentially within the step cycle (1) and reach their peaks in different phases of the cycle (159, 203) (see Fig. 4E). The P2 responses are also seen without preceding P1 responses. In GL of intact cats, short latency responses (10 ms) were observed during swing (1, 203), although these were not seen by all investigators (159, 462). A similar pattern of response was also observed in decerebrate cats (161, 203). Stimuli applied during the ipsilateral swing also gives rise to P2 responses in the contralateral limb of decerebrate cats (159) and chronic spinal cats (207). In the latter, the crossed extension reflex usually had a shorter latency than the ipsilateral excitatory responses observed in extensors (see below). Finally, crossed flexor as well as crossed extensor responses occur in decerebrate (216) and intact cats (159, 160), again suggesting a variety of crossed cutaneous pathways (268) leading to the phase-dependent activation of antagonist motoneuron pools.
The period of reflex responsiveness in a given muscle does not necessarily coincide with the period of locomotor activation of the muscle. For instance, P2 in St may reach its maximal amplitude before the muscle is activated. P1 responses may also be present well after the first St burst has ended (207) and are often absent during the second St burst which occurs at foot contact. Such discrepancies have also been well documented also by others (439) using stimulation of dorsal root filaments and recording from muscles such as St, flexor hallucis longus (FHL) (410), and extensor digitorum longus (EDL). There is thus good evidence that the reflex modulation during locomotion does not primarily result from an automatic gain control of reflexes, i.e., a condition in which reflex amplitude would simply follow the amplitude changes of the underlying locomotor EMG (see Fig. 4). Similar evidence obtained in the forelimbs will be reviewed later and will be discussed more thoroughly in section IV. Moreover, the reflex excitability and locomotor recruitment of distal hindlimb muscles may be significantly different among animals, and this may be related to the variability of mechanical action of certain muscles in different animals (350).
ii) Stance phase. Electrical stimulation during stance also gives a rather complex sequence of responses. In the intact cat, stimulation of the dorsum of the foot or specific cutaneous nerves evokes predominantly a short latency inhibition followed by a longer latency excitatory response at a P2 or P3 latency (35 ms) (1, 32, 159, 203, 207, 350, 462). This short latency inhibition is less pronounced in chronic spinal cats (203), and even shorter latency excitatory responses appear in gastrocnemius medialis (GM) and flexor digitorum longus (FDL) with sural nerve stimulation (1) and sometimes in vastus medialis (VM) motor units (356). It is of interest to link these observations to previous studies that have described short latency excitatory pathways from cutaneous afferents to extensor motoneurons (69, 201, 258, 322, 323, 595). Therefore, the predominance of short latency inhibitory responses in intact cats and the often preponderant excitatory responses in spinal cats might simply reflect the fact that multiple alternate pathways are recruited by these stimuli and that the transmission in the various pathways may vary according to the preparations (268). At longer latency, the effects of cutaneous inputs from the hindpaws (pads and sural territory) are predominantly excitatory to extensor muscles during locomotion (161, 201, 344).
The dominant excitatory effects on extensor muscles from the foot may participate in the regulation of stance together with muscle proprioceptors as will be discussed in more details below (161). On the other hand, if a moving object touches the dorsum of the foot, the excitatory responses in extensors may serve to push the foot backwards and shorten the stance to reduce the period of contact with the obstacle. Furthermore, an object touching the foot laterally in the receptive field of the caudal sural nerve can generate responses in GM to remove the foot in a specific direction. These responses would be related to specific excitatory pathways from sural nerve to GM (304, 322). Such site-specific responses (classically described as local sign) elicited during locomotion (157, 159, 163) would thus be highly purposeful. A series of experiments in the rat suggested that precise withdrawal patterns of the foot were subserved by an elaborate set of spinal modules (519, 520) that could play a role in avoidance responses during locomotion. Such an organization has also been suggested to be present in humans, as will be discussed below.
iii) Effects of phasic stimuli on overall changes of the step cycle. One remarkable function of complex phase-dependent responses is to optimize the compensatory movements and minimize perturbation of walking. If flexion reflex responses to the stimulation of the dorsum of the foot would occur in stance, that is, when the foot is on the ground and the contralateral limb is swinging forward, profound perturbations of the rhythm would ensue. In such case, the stimulated limb would rapidly flex and curtail the stance phase, while the contralateral limb would have to rapidly be brought downward to support weight. This is not the case with the responses described here in which flexion responses are inhibited during stance or replaced by ipsilateral extension. Therefore, the kinematic changes are limited to the on-going phase, and the corrections are over within one step cycle (156, 216). Stimulation of the dorsum of the foot during swing in the chronic spinal cat (207) usually slightly increases the duration of that phase. Stimulation in E3 may shorten the cycle up to 20%. The contralateral cycle is only slightly changed. Similarly, in the thalamic cats, stimulation of the foot pad or sural nerve shortened the ipsilateral cycle by 10–15% unless applied in early swing and in the late stance phase (157, 161). In the intact cat (203) there are only very limited changes in cycle duration. Therefore, these well-adapted phase-dependent reflex responses allow corrections to occur within the locomotor phase where they occur and minimize the perturbation to the overall locomotor progression.
iv) Phase-dependent responses in fictive locomotion. It is of interest to ask whether the phase-dependent modulation of reflex responses results from cyclical changes of central excitability or from concomitant interactions with afferents activated during locomotor movements of the limbs themselves. This was addressed using preparations with fictive locomotion in which there is no movement.
During fictive locomotion induced by noradrenergic drugs in cats spinalized a week before an acute experiment (321), the amplitude of short latency reflexes was also modulated in a phase-dependent manner. Specific cutaneous nerves were stimulated, and the response pattern to stimulation of low-threshold afferents was determined in various flexor and extensor muscle nerves. As was described before for real locomotion, phase-dependent reversal was shown, i.e., the same stimulus producing a short-latency excitation in the flexor St during and somewhat after its period of activity and excitatory responses in ankle extensor nerves in the opposite phase, with a predominance of some inputs from specific cutaneous nerves to certain motoneuronal pools. P1 and P2 responses could clearly be seen in these spinal cats, and their respective amplitude modulation was different in the various phases of the fictive locomotor cycle. The importance of this study, as well as that of others (8) in paralyzed cats, was to show that these refined dynamic interactions rely on central mechanisms rather than on concomitant afferent mechanisms as could be the case when sensory afferents are activated during real movements of the limbs.
The extent of complex central mechanisms in phase-dependent reflex modulation was highlighted by an important study that illustrated the differential responsiveness of two synergistic muscles during fictive locomotion. Anatomically, the FDL muscle acts as an extensor of the toes in parallel with the FHL muscle. However, during stepping, FHL is active as an antigravity muscle during the extensor phase, whereas FDL is active in early flexion except for rare bursts of activity in extension presumably associated with perturbed steps (410). This difference is striking because FDL and FHL share common monosynaptic Ia excitation (201), which is usually an indication of synergistic action (177). During fictive locomotion, intracellular recordings show that disynaptic excitation from superficial peroneal (SP) to FDL is facilitated in early flexion, when FDL is bursting and motoneurons depolarized (510), whereas di- and trisynaptic excitation from the medial plantar nerve (MPL) innervating the ventral surface of the foot is depressed. However, the trisynaptic excitation from the MPL nerve is enhanced during extension in unusual or perturbed steps when FDL fires in extension (201, 394). In contrast, the SP responses in FHL motoneurons consisted mainly of inhibitory postsynaptic potentials (IPSPs) with little or no excitatory postsynaptic potentials (EPSPs) (201). These contrasting modulation patterns and the ensemble of results on these pathways indicate that SP and MPL cutaneous inputs to FDL cells are transmitted through completely different sets of interneurons that can be driven by the CPG (67, 68). Remarkably, the excitation in FDL is trisynaptic at rest or in extension but disynaptic in early flexion. The stimulation of the red nucleus or pyramidal tract can also decrease the latency of cutaneous responses in FDL motoneurons (510, 510). However, disynaptic linkage is also seen during rhythmic activities in spinal cats injected with nialamide and L-DOPA (510), and the spinal mechanism rerouting the SP inputs onto the last-order interneurons is unknown. Candidate interneurons have been located in laminae V and VI of segments L6 and upper L7 (395), but there are yet no recordings during fictive locomotion.
Short-latency responses to SP and MPL inputs were also studied in motoneurons of EDL and TA, two synergist ankle flexor muscles (120). In EDL motoneurons, SP evoked mostly disynaptic IPSPs in early flexion and had very little effect in extension or at rest. EDL motoneurons are depolarized in mid and late flexion. In contrast, SP produced oligosynaptic EPSPs at rest and also during extension in TA motoneurons, but these were suppressed in flexion. On the other hand, MPL evoked disynaptic EPSPs in both EDL and TA cells that were suppressed in flexion. Together with previous data, the MPL excitation is suppressed in FDL, EDL, and TA cells during flexion, and common interneurons may be involved in these pathways. Also, SP interneurons projecting to FDL and EDL appear to be driven during flexion. Moreover, disynaptic EPSPs in FDL and IPSPs in EDL are enhanced during the early flexion phase of fictive locomotion, but markedly depressed during fictive scratching indicating a clear state-dependent transmission in these pathways (121, 121).
Two recent papers by the group of McCrea (469, 470) have extended significantly our knowledge of the spinal pathways involved in stumbling corrections evoked in the flexion phase or the preventive stumbling reactions triggered by the same stimulation applied during the extension phase. The first remarkable finding is that the details of functional stumbling responses can be observed during fictive locomotion evoked by mesencephalic locomotor region (MLR) stimulation (see sect. III) in the decerebrate cat (469) by stimulating the superficial peroneal nerve with trains of pulses and recording several nerves acting at the various hindlimb joints. Fist, the ankle (except TA which is briefly activated) and hip flexors are initially inhibited (possibly to prevent further contact with the stimulus). This is followed by a knee flexion and ankle extension to actively remove the foot and then a later activation of flexors at different joints that would presumably bring the limb in front of the obstacle. Interestingly, the cutaneous nerve stimulation applied during stance also evoked excitatory responses in ongoing extensor muscle nerves (see also Ref. 321) and a subsequent large activation of the hindlimb flexor discharges in the next flexor phase of the fictive locomotor cycle. Corresponding intracellular events were also recorded from various types of motoneurons (470). Of great interest in this study is the predominance of di- and trisynaptic excitation of knee flexor and ankle extensor motoneurons. Concerning the latter, the excitation starts at the same time as in the knee flexors, but the actual motoneuronal discharges (and hence electroneurographic responses) are somewhat delayed because this excitation first has to offset the locomotor-related hyperpolarization of the extensor motorneurons in that phase. There is also a clear increase in amplitude of IPSPs in ankle flexor motoneurons and a reduced inhibition of extensors. Finally, late responses occurring in the following flexor phase after a stimulus applied in the previous extensor phase are thought to represent complex responses evoked by the SP nerve through the CPG.
Together, these intracellular studies of motoneurons clearly suggest complex mechanisms of reflex pathway selection (see Fig. 1) by which afferents reaching synergistic muscles give rise to appropriate phase-dependent responses either through the CPG itself or through interneuronal pathways whose excitability is modulated by the CPG. This is discussed further in section IVB.
II) Forelimbs. Although most studies on dynamic sensorimotor interactions were performed on the hindlimbs of cats, some studies on the forelimbs shed new light on such interactions. As was the case for the hindlimbs, cutaneous afferents of one forelimb were also removed (534), and 1 wk later the cat could walk well on the treadmill, suggesting that these afferents are not essential for the control of forelimb walking.
Responses to cutaneous stimuli of the forelimbs during unrestrained walking are also phase-dependent in intact cats (146–148, 482) and thalamic cats (535). Figure 5 illustrates an interesting combination of responses to electrical stimulation of the superficial radial nerve during the swing and stance phases in four muscles with different biomechanical actions at different joints. Figure 5 illustrates, with raw EMGs (on the left side), typical responses evoked by a single stimulus given during either the swing or stance phases (left column). The responses to 10 stimuli given in swing and stance are displayed in a raster form in the two middle columns to illustrate their general phase dependency. On the right of Figure 5, A–D, the responses are plotted as a function of the cycle phase using the method described in Figure 4. Note that the duration of activity of other muscles acting at the same joint are also displayed (open bars) on the right side for comparison. The latissimus dorsi muscle (a shoulder retractor) has a large response to the stimulation of the radial nerve during swing but is unresponsive during stance. On the other hand, there is a large excitatory response in triceps brachii (long head, elbow extensor) during swing where this muscle is normally inactive during locomotion and an inhibitory response during the stance phase. As mentioned previously for the hindlimb, when the forelimb hits an obstacle the elbow flexors and extensors are strongly coactivated leading to a virtual lock of the elbow while the shoulder retracts the limb first and then, at a longer latency, the shoulder protracts and brings the limb in front of the obstacle. The large out-of-phase excitatory response in triceps during swing, in a period where this muscle is inactive during locomotion, indicates again that the reflex responsiveness of a muscle may be under separate control from its locomotor activation. In Figure 5C, the elbow flexor yields an important excitatory response during swing followed by a clear inhibition and is unresponsive during stance. Palmaris longus (Fig. 5D), which is normally active during stance, shows a large response in swing and a slight excitatory response during stance followed by inhibition. These responses are undoubtedly related to the positioning of the foot.
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It is of interest to mention that, during fictive locomotion, when there is no movement, the out-of-phase responses occurring in triceps could not be observed (504) and only excitatory responses during the period of locomotor activity obtained with stimuli applied to the superficial radial nerve. This might implicate that, for this particular cutaneous pathway, the out-of-phase responses may depend on a balance between central drive and concomitant peripheral inputs generated during active locomotor movements.
D) ELECTRICAL STIMULATION OF CUTANEOUS AFFERENTS IN HUMANS. In humans, nonnociceptive electrical stimulation during walking also yields phase-dependent responses that induce withdrawal responses during swing and stabilizing responses during stance (610) (see Fig. 3, B and C). As was indicated in previous animal work (206, 207), such phase-dependent reflex reversal makes functional sense. For instance, tibial nerve stimulation, which mimics a stimulation of the plantar surface of the foot (Fig. 3B, left), yields an ankle flexion at the stance to swing transition to remove the foot, whereas it produces an ankle extension in late swing (Fig. 3B, right) to accelerate foot placement on the ground (165, 610). Stimulation of SP, resembling a stimulation of the dorsum of the foot such as when encountering an obstacle, produces a suppressive response in TA in early swing which translates mechanically into a plantar-flexion, whereas there is an excitatory response in SOL, GL, and GM later in swing (610) (Fig. 3B, middle). If the stimulation evokes a larger flexion of the ankle, it could increase the likelihood that the foot would catch the obstacle instead of clearing the obstacle (168). Thus the site of cutaneous stimulation determines largely the type of functional reflex responses evoked to clear an obstacle or to prevent further contact with the obstacle. Other studies, stimulation during stance of the sural nerve which innervates the lateral part of the foot, have shown (165, 612) an activation of GM and TA, and these responses are believed to result in a dorsi-flexion and eversion of the foot (see large arrow in Fig. 3C, right). Presuming that the sural nerve stimulation here mimics a stimulation of the lateral part of the foot on an uneven terrain, the eversion response would counteract the inward displacement. During swing, the responses to sural stimulation in the ankle and knee flexors would serve to avoid the obstacle.
Although the description of responses has focused mainly on the corrective movements of the ankle, more proximal joints such as the knee and hip were also involved in the evoked reflex responses. There is an interesting difference between quadrupeds such as the cat and humans. In cats, as mentioned earlier, one important strategy is to lock the distal joint and move the foot through flexion at more proximal joints. In humans, in addition to inducing responses in ankle muscles, stimulation of SP, tibial, and sural nerves all give responses in knee muscles such as the knee extensor vastus lateralis (VL) and knee flexor BF with, however, a resultant knee flexion. The role of the coactivated knee extensor is not clear, although it is postulated to limit the flexion of the knee, which could be destabilizing (610, 612). Therefore, these corrective reactions result in complex movements involving multiple joints (also contralateral) that have to be optimally integrated in the locomotor movement.
Similarly to what was done in cats during forward and backward walking, electrical stimulation of the sural nerve at twice the strength needed to evoke a motor response was applied during forward and backward walking in humans (164). Excitatory and inhibitory responses were seen in both forms of walking but at different times in the cycle corresponding to the biomechanical roles of the muscles in the different tasks. Cutaneous reflexes are generally increased during running compared with standing or tonic contraction (166).
In summary then, although cutaneous inputs have some general roles in facilitating or inhibiting locomotion, they appear to be involved in the correct positioning of the limb (foot) during normal locomotion or after perturbations induced by mechanical obstruction or electrical skin stimulation.
As for cutaneous afferents, muscle afferents have general roles such as providing signals acting as on-off switch to set the range of joint angular excursion within which locomotion can take place. However, an important role of muscle afferent feedback appears to be in setting the overall timing of the step cycle by adjusting the duration of the various phases of the locomotor cycle and facilitating the switch between these phases. Another important role is to regulate the output amplitude of muscles in various phases. This section reports the observations made in animal preparations or humans and, when appropriate, discuss more specific spinal proprioceptive pathways that could be involved in mediating these effects.
1. Initiating and blocking the locomotor rhythm
Locomotor movements can only operate efficiently within a certain range of limb position. Outside this range little force can be applied by the feet or the feet may simply lose contact with the walking surface. Afferents signaling the amount of stretch in muscles acting at various joints must therefore play a key role in setting the limits of limb position within which locomotion can occur. Such a role has been demonstrated experimentally in different manners. Early work (532) suggests that hip proprioceptors exert a powerful control over the initiation of the locomotor rhythm because extending the hip in a spinal animal is sufficient to initiate air stepping, whereas flexing the hip can prevent it. Similarly, in chronic spinal cats, flexion of the hip joint on one side can abolish treadmill stepping on that side, whereas the other sid
