reflex modulation during rhythmic limb movements in humans

J Phys Fitness Sports Med, 1(1): 37-49 (2012)

JPFSM: Review Article

Reflex modulation during rhythmic limb movements in humans

Tomoyoshi Komiyama1,2* and Tsuyoshi Nakajima3

1 Department of Health and Sports Sciences, Faculty of Education, Chiba University, Chiba 263-8522, Japan2 Division of Health and Sport Education, The United Graduate School of Education, Tokyo Gakugei University, Tokyo

184-8501, Japan3 Department of Integrative Physiology, Kyorin University, School of Medicine, Tokyo 181-8611, Japan

Received: March 9, 2012 / Accepted: April 11, 2012

Abstract For many locomotor behaviors, such as walking or running, we count on subliminal somatosensory information to smoothly maintain on-going movement and avoid falling down when disturbances are presented to the stability of the body. Reflex responses induced by disturbances to stability play important roles in generating quick corrective responses. Reflex outputs to the arm and leg muscles generated by muscle and cutaneous afferents during locomotor movement show quite different features compared to those generated by simple voluntary contraction during sitting or standing, irrespective of the similar background activity of motoneurons. In particular, the excitability of cutaneous reflex pathways elicited by the electrical stimulation of low threshold mechanoreceptors on the skin is strongly modulated in a phase-, nerve-, task-dependent manner during locomotor movement. The pattern generating system in the spinal cord, which has been studied intensively in quadrupedal animals, may be responsible for both generating locomotor movement and reflex modulation even in humans. However, due to methodological difficulties, the accumulated evidence derived from human experiments is indirect. In this review, we will outline these unique features of the cutaneous reflexes during locomotor and rhythmic movements in humans.Keywords : reflex modulation, rhythmic limb movements, central pattern generator, walking,

cycling, cutaneous reflexes

Introduction

Around a century ago, original physiological evidence indicating the possible contribution of neural connections subserving intralimb and interlimb reflexes to locomotion was provided by Sir Charles Sherrington with decelerated cats1,2). Later, it was shown in cats that stimulation of the cutaneous nerve produces general flexor excitation with the exception of muscles directly beneath the stimulated region of the skin. This reflex pattern was named “local sign” 3), and produces withdrawal responses to direct the limb away from noxious cutaneous stimuli 4). Noxious re-flexes are therefore thought to be indicative of a modular organization of the spinal cord to produce a seminal func-tional outcome during locomotion in response to noxious sensation5). Different from the noxious reflexes, cutaneous afferents arising from low threshold mechanoreceptors existing un-der the skin surface can give rise to widespread and seg-mental excitatory and suppressive reflex effects in various motoneuron pools (cutaneous reflexes for review, see6-8)) To date, the cutaneous reflexes in human hand muscles

have been demonstrated to be modulated in a task-, age- and pathological-dependent manner9-13). Interestingly, the functionally relevant reflexes occur during human walk-ing14,15). In this review, we will discuss the nature and functional significance of the intralimb and interlimb cu-taneous reflexes during locomotor movements in humans. In addition, modulation of monosynaptic spinal reflex (Hoffmann (H-) reflex) during rhythmic movement will also be discussed as necessary.

Methodological considerations

1. Neurophysiological bases of reflex responses arising from cutaneous afferents Cutaneous reflexes in first dorsal interosseous (FDI) are triphasic, consisting of an initial short latency excita-tion (E1), followed by inhibition (I1), then followed by a prominent long latency excitation (E2). An electrophysi-ological estimation of the central delay and the ascending and descending conduction time of E1 and E2 suggests that they are mediated by distinct reflex pathways11,12). In particular, E2 is absent in patients with damage to the mo-tor cortex, but E1 remains in these subjects. In addition, E2 is reduced in amplitude and often delayed in patients *Correspondence: [email protected]

38 JPFSM : Komiyama T, et al.

with motoneuron disease causing damage to the cortico-spinal tract 12). From these observations, it was concluded that E1 has a spinal pathway; and E2 is of supraspinal origin requiring transmission of afferent impulses through the dorsal columns, a relay in the sensorimotor cortex, and descending transmission to the lower motoneuron pool by way of the corticospinal tract 12). To date, cutane-ous reflexes have been shown to be modulated in an age-, task-, and training- dependent manner 9,10,13). Cutaneous reflexes can be elicited in leg (hindlimb in quadrupeds) muscles as well. Contact between the dorsum of the hindlimb paw and an obstacle during the swing phase of locomotion in the cat evokes coordinated ankle flexion and knee extension in an attempt to avoid tripping16,17). These reflex patterns have been termed “stumbling corrective reaction”. Also, coordinated muscle activation in intra- and intersegments following stimula-tion of the skin during on-going locomotor activities was shown in cats 5,18,19). Similar reflex patterns are observed in forearm, upper arm and leg muscles following the stimulation of cutaneous nerves in humans20,21). Short latency excitatory responses are usually very small and sometimes indiscernible in sitting or quiet standing pos-tures22,23). However, short latency excitatory responses are facilitated when subjects stand on an unstable surface, suggesting that the short latency component of the cu-taneous reflex in leg muscles is strongly modulated in a context-dependent manner. It is worthy to note that the cutaneous reflexes at a given latency can be reversed from excitatory to inhibitory depending on phase or task 22). Reflex reversal is thought to be an outcome of parallel inputs to motoneurons from distinct excitatory and inhibi-tory interneurons, which receive excitatory inputs from both descending and ascending systems24,25). In addition, these discrete reflex pathways would be differentially regulated depending on a given task. To date, there is no tangible evidence showing that the short latency cutane-ous reflexes in leg muscles are mediated solely by spinal circuitry26). Recent advances in the study of interlimb reflexes in hu-mans have provided ample evidence suggesting that cuta-neous reflexes are crucial for generating rapid compensa-tory movements in remote limbs in response to a sudden disturbance of limb movement during various locomotor activities 6,8,15,27-30). Intralimb cutaneous reflexes have been demonstrated to possess task dependency (phasic locomo-tor vs. tonic maintained activity), intensity dependency (noxious vs. non-noxious stimulation), load dependency, phase dependency (swing vs. stance), and laterality de-pendency (ipsilateral vs. contralateral effects)6-8). The am-plitude of cutaneous reflexes in both arm and leg muscles strongly depends on the location of the skin in which the stimulation was delivered (location specificity)31-33). These previous studies indicate that cutaneous reflexes are of functional importance for a variety of rhythmic move-ments for on-going activity in response to tactile sensa-

tion. In addition, distinct reflex patterns during stationary contraction and locomotor activity strongly suggest an in-volvement of pattern generating systems in limb muscles, as has been observed in quadrupedal animals34-36).

2. Pattern generating system Locomotor activities such as walking, running and swimming involve distinct rhythmic patterns of arm and leg motions. In a considerable number of invertebrate and vertebrate preparations, neuronal activity related to central pattern generating (CPG) circuits in the spinal cord for rhythmic locomotor movement has been identi-fied 8,37-40). Brown41) first demonstrated a neural system in the lumbar spinal cord that generated oscillation of alter-native flexor and extensor activity41). The neural center, termed “half-center”, is thought to be a key system for CPG, which produces the basic locomotor rhythm8,37,42,43). CPG produces alternative flexor and extensor activ-ity without input from descending motor and ascending sensory inputs because locomotor rhythm can be gener-ated in deafferented and spinalized (fictive locomotion) preparations42-44). Therefore, the term CPG should be used only to refer to spinal circuits capable of generat-ing an organized bilateral rhythmic pattern in the absence of descending and sensory inputs44). Indeed, in acutely spinalized and paralyzed cats, a well-organized rhythmic output can be recorded directly from flexor or extensor nerves with pharmacological stimulation (L-DOPA) in the complete absence of overt movement 44,45). As shown in Fig. 1, a given level of the spinal cord involves some key features of locomotor control, consisting of CPG, several descending pathways such as corticospinal and re-ticulospinal tracts, neurochemically defined pathways that release neuromodulators such as norepinephrine (NE) or serotonin (5-HT), and afferents from peripheral sensory receptors44). Contusion and pharmacological preparations were used to determine the seminal localization of rhythmogenesis in the spinal cord. Although rhythmogenic properties within the lumbosacral spinal cord are distributed over several segments, the L3-L4 segments in cats,46-48) and L1-L2 segments in rodents 42,49) are critical for rhythm genera-tion. Inactivating or damaging these segments will gener-ally abolish or severely impair locomotion,44). In contrast to the lumbar enlargement, Ballion et al.50) found a caudo-rostral gradient for rhythmogenesis in the cervical en-largement of the isolated neonatal rat spinal cord. Juvin et al.51) suggested that while C5 through C8 are rhythmo-genic, they can be driven by the lumbar pattern generat-ing circuitry in a longitudinally intact preparation52). A number of authors have proposed that long propriospinal axons are likely candidates for the functional coupling of the cervical and lumbar CPG networks and the mediation of interlimb coordination18,19,52,53). Electrically stimulating the pyramidal tract during fic-tive locomotion in the adult cat can reset the hindlimb

39JPFSM : Reflex modulation during rhythmic limb movements

ing commands that converge to subcortical regions such as the cerebellum, basal ganglia and brain stem to shape the required motor program. Of these, the mecencephalic locomotor region (MLR) in the midbrain plays a crucial role in generating basic oscillatory signals for rhythmic limb movements. Signals from the MLR are known to drive the CPG in the spinal cord 37,38,44,56). In investigating the nature of intra- or interlimb reflexes during locomotion in humans, a myriad of rhythmic arm and leg movements can be utilized as motor tasks. Walk-ing (including down- or up-slope), stepping, running, creeping, swimming, and ergometer cycling have been used as locomotor models 8,37,61). In addition, the excitabil-ity of reflexes was investigated during various movement phases of these locomotor models. To effectively reveal the nature of intra- and interlimb reflexes during locomo-tor activity in humans, the categorization of movement would be beneficial. A Canadian research group, headed by E. Paul Zehr, has intensely studied the modulation of reflexes elicited by stimulating somatosensory afferents during three basic patterns of rhythmic locomotor move-ments: isolated arm or leg cycling, arm and leg stepping or cycling, and treadmill walking62). They proposed a basic common feature of modulation of the cutaneous or spinal monosynaptic H-reflexes during these rhythmic movements, and concluded that there is a common core that formulates recruitment of the muscles and reflex patterns to be used during different types of rhythmic movements (Fig. 2)62). These findings imply that we can utilize an optimal motor task from three basic patterns to

rhythm, indicating that the corticospinal tract has direct access to the rhythm-generating circuitry54). In addition, group I ankle extensor afferents from the foot appear to have direct access to the rhythm-generating circuitry of the spinal locomotor CPG, which was inferred by their ability to reset or entrain the fictive locomotor rhythm in adult cats 44,55-57). Cutaneous inputs from the plantar surface of the paw can also reinforce extensor activity in decerebrate cats walking on a treadmill58) or during fictive locomotion59). The results of these studies indicate that CPG receives various inputs from the descending and as-cending system and can be modulated in concert with the locomotor environment or task requirements. CPG not only acts as a generator of basic locomotor rhythm, it also plays a crucial role in regulating the gain of reflex pathways, which gives rise to quick corrective behaviors in response to somatosensory inputs60). The higher motor center likely sends driving commands to CPG; and, then, the gain of many reflex pathways is regu-lated by CPG to cope with the various modes of distur-bances through the somatosensory system.

3. Common core system generating rhythmic move-ment and modulator for reflex pathways Human subjects can perform a wide range of rhyth-mic arm and leg movements easily, which is beneficial in adapting to different physical or environmental con-straints during locomotion. For a basic stratagem to per-sist locomotion in different environments, the brain must select an optimal movement pattern and trigger descend-

Fig. 1 General framework of locomotor control as described by Rossignol and Frigon44). F and E, flexor and extensor motoneurons; DLF, dorsolateral funiculus; VLF, ventrolateral funiculus; NE, nor-epinephrine; 5-HT, serotonin; GLU, glutamate (GLU); Ach, acetylcholine; DC, dorsal columns; DRG, dorsal root ganglion. For detailed explanations, see Rossignol and Frigon44).


ing leg pedaling tasks. In leg muscles, cutaneous reflexes following sural nerve stimulation are strongly modulated in a phase-dependent manner depending on the biomechanical function of the limb muscles during cycling68). Also, modulation of the H-reflex and cutaneous reflexes evoked in forearm mus-cles are dependent on the movement phase during rhyth-mic arm movement 29,30). Furthermore, although the size of the reflexes is proportional to the background EMG in a stationary condition, the relationship becomes ambiguous during cycling21,30,69). One of the underlying mechanisms for these reflex modulations may be regulation at the premotoneuronal level. Frigon et al.70) demonstrated that sural nerve stimulation facilitated H-reflexes in the soleus (Sol) at shoulder extension, but not at shoulder flexion during static and arm cycling, and that common peroneal nerve (CP) stimulation significantly reduced Sol H-reflex amplitude during static and cycling tasks (see Fig. 3). Reflexes in the soleus when sural and CP nerve stimula-tion were delivered alone, did not differ between cycling and static trials. Thus, it is likely that the task-dependent changes in H-reflex amplitude are irrelevant to motoneu-ron excitability. Therefore, the modulation occurred at a pre-motoneuronal level, probably by presynaptic inhibi-tion of the Ia afferent volley. It may be that neural net-works coupling the cervical and lumbosacral spinal cord in humans are active during rhythmic arm movement, and activation of these networks may assist in reflex linkages between the arms and legs during locomotor tasks. These results suggest a contribution of the pattern generating system in the spinal cord to the regulation of locomotor activity not only in the legs, but also in the arms. Taking together, rhythmic arm and/or leg cycling can be used as a tool for investigating the function of CPG in humans.

Reflex modulations of cutaneous reflexes in arm mus-cles during rhythmic movements

In humans, the evolution of an upright stance and bi-pedal gait has allowed for a great deal of flexibility in how the arms interact with each other and how combined arm and hand action can manipulate objects. At the same time, cortical control of arm muscles has been largely consolidated in the process of evolution with strengthen-ing the monosynaptic connections between pyramidal tract cells and both motoneurons and propriospinal neu-rons located at C3-C5 segments71). Also, the reflex system is differentially organized between arm and leg to adapt to different environmental and biomechanical requirements. In particular, CPG regulation of the reflex system for arm and leg may be differentially organized because of their functional differences in manipulation and locomotion72). However, evidence suggests that there are some similari-ties and dissimilarities of reflex control between the arms and legs during cyclic movement.

investigate the role of CPG as a modulator of somatosen-sory reflexes depending on the objective of the research. If possible, changes in load using counter weights, water immersion, and changes in axial resistance load can be used to investigate the nature of the CPG system in hu-mans6,7,61,63).

4. Differential regulation of the excitability of the motoneuron pool and reflex pathways during static muscle contraction and rhythmic movements During stationary contraction, the excitability of spinal reflexes are automatically tuned in accordance with the level of motoneuronal excitability64). However, during rhythmic movements, the gain of monosynaptic spinal reflexes is differentially regulated from the excitability of the motoneuron pool for the homonymous muscle. Brooke et al. conducted extensive research examining the regulation of reflex pathways during passive cycling or stepping in humans. They showed that passive movement of the leg in a pedaling motion leads to a profound inhibi-tion of the reflex in the moving leg and the contralateral leg at rest 65-67). They also showed that the magnitude of H-reflex inhibition was dependent on the phase position and the estimated rate of stretch of the extensors of the knee and hip. They showed that an increasing speed of passive rotation increased the inhibition at all positions, but was most pronounced near the fullest flexion of hip and knee. Pedaling-like passive movement of merely the hip or knee joint also results in substantial inhibition of the reflex61,65). The results of these studies suggest that activation of somatosensory afferents, likely from muscle mechanoreceptors excited by the movement, leads to the inhibition of reflex transmission, which appears to be ir-relevant of the excitability of the motoneuron pool. Thus, afferent inflow from muscle spindles to the motoneuron is confined by premotoneuronal mechanisms, most probably by presynaptic inhibition driven by the CPG system dur-

Fig. 2 Schematic conceptual overview of the regulation of rhythmic human movement provided by Zehr et al.62,77)


1. Reflex modulations during arm cycling The CPG system in humans may contribute as much to the control of rhythmic arm movement during locomotor movement as it does to cyclic leg movement. The rhyth-mic arm swing during human locomotion has been sug-gested to be a functional outcome resulting from muscle activation, and not a passive pendular movement due to mechanical interaction with leg and trunk motion73-75). Recent locomotor research in humans suggests that CPG plays an important role in generating muscle activation and in reflex regulation of arm movements, and may share common features with those in quadrupedal ani-mals 6,8,76-78). It has been documented that, during rhythmic arm movement, the cutaneous reflex amplitude follows

stimulation of the superficial radial nerve co-varied with background EMG (background-dependent modulation)79). This is in contrast to the pattern seen in the leg muscles in which there is often a dissociation between reflex am-plitude and EMG level 14,80). Later, however, a significant background dependency could not be demonstrated 30,81,82). In some arm muscles, the position of the limb during arm cycling influenced the size of the cutaneous reflex responses in a manner that was independent of the back-ground EMG activity. The middle latency cutaneous reflexes were facilitatory during static contraction, but at-tenuated dramatically. In addition, cutaneous stimulation resulted in an excitatory response at some points in the arm cycle, but inhibition at other points of the cycle (re-flex reversals)30). Reflex reversals also occurred in some

Fig. 3 Modulation of H-reflex in the soleus during arm cycling, and effects of somatosensory conditioning stimulation. Conditioning stimulation to the common peroneal nerve (CP) and sural nerve stimulation suppresses and facili-tates the H-reflex amplitude during arm cycling. For detail, see Frigon et al.70).


muscles between static contractions and rhythmic move-ments 24,30,39,83). Reflex pathways mediating the cutaneous reflex may receive parallel excitatory and suppressive inputs, and are under the control of descending and as-cending systems in addition to the CPG system (see Fig. 1 and 2). Thus, the reflex outputs are flexibly modulated in phase-dependent, posture-dependent, nerve-specific, task-dependent and context-dependent manners. It is important to consider these factors when interpreting the functional significance of cutaneous reflexes during the variety of rhythmic arm movements.

2. Left-right coupling of arms during rhythmic movement Muscle activity on the left and right side of the body is precisely coordinated during locomotion to secure al-ternation of corresponding muscles on either side of the body as seen during walking42). The neuronal circuits responsible for left-right coordination are commissural in-terneurons, whose axons cross the midline via the ventral commissure and which have been studied extensively in the rodent and cat spinal cord 42,84). A dual intrasegmental commissural interneuron (sCIN) system was demon-strated that inhibits segmental motor neurons via poly-synaptic inhibition. Polysynaptic inhibition is mediated by glutamatergic sCINs and local ipsilaterally-projecting inhibitory interneurons, including Renshaw cells and Ia inhibitory interneurons; and monosynaptic inhibition is mediated via glycinergic/GABAergic sCINs. In addi-tion to the inhibitory pathways, glutamatergic sCINs can excite motor neurons directly42). In humans, the nature of coupling between CPGs for the left and right arms is of significant interest as a basis for comparison of the mechanisms of neural control between arm and leg move-ments. It was reported that H-reflexes are not depressed in a stationary arm when the contralateral arm is moved in a cyclical manner, which clearly differed from the regula-tion of H-reflexes in legs29,85). In addition, Carrol et al.81) investigated the nature and degree of coupling between the upper limbs during arm cycling, with regard to the regulation of cutaneous reflexes, and found that the pat-tern of cutaneous reflex modulation throughout the arm cycle was independent of the functional state of the limb contralateral to the recording site, irrespective of whether recordings were made ipsilateral or contralateral to the stimulation. Such weak contralateral effects suggests that the strength of the neural coupling between the arms is weaker than between the legs (loose coupling), at least in terms of the regulation of muscle afferent reflexes (Fig. 4).

3. Similarity of modulation of cutaneous reflexes in arm and leg muscles during arm cycling Once the arm begins rhythmic cyclical movement, the amplitude of cutaneous reflexes recorded from muscles in the moving arm is strongly modulated in a phase- and task-dependent manner 21,30). In addition, amplitudes of both early and middle latency cutaneous reflexes are mod-

ulated similarly, irrespective of arm cycling direction (for-ward or backward cycling)86). That is, at similar phases in the movement cycle, responses of corresponding sign and amplitude were observed regardless of movement direc-tion. In general, these findings are parallel to observations in leg muscles after stimulation of cutaneous nerves in the foot during forward and backward walking, which ap-pears to be further evidence for CPG activity contributing to neural activation and reflex modulation during rhyth-mic arm movement 30,69,86). Thus, control mechanisms un-derlying the modulation of cutaneous reflex amplitude in arm muscles during rhythmic arm movement are thought to be similar to those reflex modulations in the leg. These findings suggest that cutaneous reflexes are under simi-lar control of CPG in the upper and lower limbs, which implicates similar motor control mechanisms under the variety of locomotor constraints.

Modulation of cutaneous reflexes in leg muscles dur-ing walking and cycling

Cutaneous reflexes, particularly those arising from stim-ulation of the sural nerve (innervating the lateral border of the foot), the tibial nerve (innervating the ventral foot surface) and superficial peroneal nerve (innervating the dorsal surface of the foot), have been studied extensively in humans and have shown phase- and task-dependent modulation of cutaneous reflexes occurring at restricted latencies 8,24,87). Initially, the extent of modulation of the

Sensoryfeed

back

Rhythmic arm and/or leg movement

Motoneurons

Interneuronal reflexnetwork

CPGLeft

CPGRight

Supraspinal (e.g. M1, SMA, CBM, MLR)

Leg

Arm

Fig. 4 Schematic illustration of the possible organization of neural mechanisms regulating rhythmic arm movement. CPG, central pattern generator; SMA, supplementary motor area; MLR, mesencephalic locomotor region; CBM, cerebellum. Adopted from Zehr et al.75).


reflex responses following stimulation of non-noxious cu-taneous nerve were examined during human walking 24,83). These studies showed a phase-dependent modulation and reversal of reflex sign from suppressive to facilitative at the end of the swing phase in tibialis anterior muscle fol-lowing tibial or sural nerve stimulation. It was argued that cutaneous reflexes play an important role in preserving balance during the step cycle.

1. Functional significance of the cutaneous reflexes during walking To elucidate the functional linkage between reflex EMG responses and kinematic outcome, EMG recordings from the upper and lower leg muscles were measured and changes in joint kinematics were also recorded 15,23,76). In addition, the total net reflex effect of stimulation and net mechanical outcome were analyzed statistically15,23,76). Reflexes to stimulation of these nerves were shown to have functional effects, particularly during swing or the swing to stance transition15,23,76). SP nerve reflexes are functionally equivalent to the stumbling corrective re-sponse described by Forssberg16) in which the swing limb passes by the imposed obstacle to maintain a relatively unperturbed step cycle. As shown in Fig. 5, during early swing, SP nerve stimulation elicited a stumble corrective response involving ankle plantar flexion and knee flexion. Tibial nerve stimulation generated a withdrawal response at the stance to swing transition and a placing response at late swing14,23). When stimulating the sural nerve during the swing phase, withdrawal of the foot from the stimulus point occurred. This was especially evident in TA and MG muscles from activation of the sural nerve because this caused a mechanical eversion and dorsiflexion of the ipsilateral foot 15). This response acts to stabilize the foot if there were pressure activation on the lateral foot border caused by uneven terrain in early stance. This response may assist in preventing an ankle sprain, which might result if excessive inversion occurred. These reflex out-comes during walking were quite different from outcomes

investigated during standing, suggesting a contribution of CPG in humans80). Haridas et al.88) examined the amplitude of cutane-ous reflexes of both the ipsilateral and contralateral legs electrically evoked from two nerves innervating differ-ent parts of the foot during walking with varying degrees of stability. They found that challenging the balance of the subjects during walking can lead to task-specific changes in reflex amplitudes, and that the influences are not related to a generalized change in reflex excitabil-ity; rather the changes observed are limited to specific reflex circuits at specific points in the step. Later, they showed that the strength of interlimb cutaneous reflexes was influenced by the level of postural threat88). Thus, the excitability of cutaneous reflexes is thought to be flexibly tuned depending on the context of a behavior.

Modulation of interlimb reflex during rhythmic move-ment

1. Neurophysiological basis of the interlimb reflexes In quadrupeds, there is a linkage between fore- and hind-limbs during locomotion19,37). Specialized neural networks in the cervical and lumber spinal cord through propriospinal circuitry are thought to be responsible for the generation of rhythmic fore- and hind-limb locomo-tor activity in quadrupeds 6,8,38-40). Coupling of both neural networks may be mediated by the long ascending and de-scending propriospinal systems in the cervical and lumber spinal cord of the cat and rat 5,18,52). Juvin et al.51) reported the pharmacological nature of propriospinal interactions between cervical and lumbar locomotor CPGs in an iso-lated newborn rat spinal cord preparation. They showed independent rhythmogenic capabilities in the cervical and lumbar locomotor regions, and an interconnection of both regions principally via propriospinal neural circuitry that extended from the rhythmogenic lumbar to cervical cord levels (see Fig. 6). They also demonstrated that both in-hibitory and excitatory synaptic pathways from the lum-

Fig. 5 Schematic summary of the major functional roles played by each group of reflexes during the human step cycle. The position of the limb is filled in black as the stick figure progresses through (left to right) four major phases of the step cycle. Note that dur-ing swing and the swing to stance transition, cutaneous reflexes are listed first while during stance and the stance to swing tran-sition muscles reflexes are listed first. This emphasizes that, while the muscle and cutaneous reflexes are likely simultaneously involved in the responses, the major contributions for each class varies with the phase of movement (see text for further details). Adopted from Zehr and Stein87).


bar generators coordinate cervical locomotor patterning, with ascending excitation playing a major role in lumbo-cervical coupling. An interesting point may be dominance in locomotor drive from the lumbar generators over the cervical counterparts, i.e., caudorostral excitability gradi-ent.

2. Interlimb reflexes in humans Reflex studies in humans have shown that interlimb reflexes may play a crucial role in coordinating arm and leg movements during locomotion6,8,89,90). It was demon-strated that there is natural frequency locking between upper and lower limb movement during walking, crawl-ing and swimming27). These findings suggest that there are substantial similarities in coordination between upper and lower limbs in bipedal humans and that of fore- and hind-limbs in quadrupeds6). However, it remains unclear how tightly the upper and lower limbs are linked during rhythmic upper and lower limb movement in humans. Zehr et al. showed that stimulation of cutaneous nerves innervating the hand (superficial radial, SR) and foot (su-perficial peroneal, SP) elicits widespread reflex responses in many muscles across the body21). These interlimb re-flex responses were suggested to be functionally relevant to assist in motor coordination between the arms and legs during motor tasks such as walking. The authors further tested the hypothesis to determine if interlimb reflexes were phase-dependently modulated and produced func-tional kinematic changes during locomotion. They found that significant phase-dependent modulation (including reflex reversals) of interlimb cutaneous reflex responses was observed in remote limb muscles. The results suggest coordinated and functionally relevant reflex pathways from the SP and SR nerves onto motoneuron innervated

muscles in non-stimulated limbs during walking (see Fig. 7). Recently, rhythmic movements other than walking were used as models for investigating the coordination between arm and leg movements in humans. Frigon et al.70) re-ported that rhythmic arm cycling alters reflex excitability in stationary legs. In addition, Huang and Ferris91) demon-strated that there was neural coupling between upper and lower limbs during recumbent stepping. They showed that rhythmic upper limb activity increased EMG amplitude in the lower limbs when subjects attempted to relax them. However, little is known about the interactions between upper and lower limbs when human subjects simultane-ously perform rhythmic arm and leg movement. If there is strong coupling of CPGs between the upper and lower limbs, cutaneous reflexes in the arm muscles can be influenced by rhythmic movement of the legs and vice versa. However, we have recently demonstrated that cutaneous reflexes in the arm muscles are little influenced by rhythmic movement of the legs, and vice versa, when subjects simultaneously performed AL cycling92). Based on these results, it was suggested that the reflex pathways responsible for the cutaneous reflexes in the arm (leg) are only weakly coupled with CPG in the leg (arm) during AL cycling. These results appear to contradict a recent perception that there is neuronal coupling of arm and leg movement during various human locomotor activities6,8,27). To further elucidate this discrepancy, we examined how coupling of both limbs is regulated during independent rhythmic movement of the arm and leg93). Subjects per-formed simultaneous arm and leg cycling (AL cycling) at their preferred cadences without feedback for 10s, and then were asked to voluntarily change the cadence (increase, decrease, or stop) of arm or leg cycling. Leg cycling cadence was not affected by voluntary changes in arm cadence. By contrast, arm cycling cadence was sig-nificantly altered when leg cycling cadence was changed. These results suggest the existence of a predominant lumbocervical rhymogenic influence of leg cycling on arm cycling during AL cycling. Taking these findings into consideration, the modulation of cutaneous reflexes dur-ing AL cycling is most probably determined by CPGs that regulate the activity of a particular limb irrespective of whether the movement of other limbs is in-phase or 180 degrees out of phase. The mutual interaction of CPGs be-tween the upper and lower limbs may be weak during AL cycling; and rhythmically or simultaneously moving the arms and legs is insufficient for a tight coupling of CPGs between the arms and legs6,92). In contrast, Balter et al.76) reported that rhythmic arm movement makes a significant phase-dependent contribu-tion to cutaneous reflex expression in the legs during a combined arm and leg task. This effect is superimposed on the dominant effect of leg movement, suggesting that there exists coupling between the arms and legs in terms of functional relationships during similar rhythmic activi-

Fig. 6 Summary diagram of asymmetrical spinal pathways contributing to the coordination of the spatially distant rhythmogenic networks underlying quadrupedal loco-motion in the neonatal rat. E, Extensor; F, flexor. Ad-opted from Juvin et al.53).


ties, such as walking. The authors further interpret this as evidence for commonalities in neural regulation among mammalian tetrapods, and that this is a predicted out-come for interactions between CPGs regulating arm and leg movement during human walking8,86). One of the most important differences between the studies by Sakamoto et al.92) and Balter et al.76) is whether there was mechani-cal coupling between arm and leg ergometers. The for-mer study was conducted with mechanically uncoupled arm and leg ergometers. In contrast, the latter study used mechanically coupled ones. This discrepancy may lead to subtle differences in strategy and motor outputs to per-form arm and leg cycling. While performing arm and leg cycling with mechanically uncoupled ergometers, a high-er motor center may differentially regulate arm and leg muscles to cope with biomechanical constraints specific to both ergometers. In addition, subjects may pay special attention to match the cadence of both arm and leg cy-cling. These factors would lead to differential regulation of CPGs through descending inputs from corticospinal and reticulospinal tracts and the cerebellum between AL cycling with coupled and uncoupled ergometers, which may explain the differential regulations of the excitability of the cutaneous reflexes.

One of difficulties to elucidating the functional cou-pling of neural circuits between the arm and leg involv-ing rhythmic and locomotion in humans may be due to different strengths of oscillatory effect from CPGs to the arms and legs. When performing rhythmic arm and leg movement, the intralimb reflex effect is much stronger than the interlimb effect. Thus, during rhythmic arm and leg movement, significant changes in the reflex effect in given limb muscles can be easily masked by phase modulation coming from the intralimb effect. Recently, we examined to what extent the excitability of the early latency cutaneous reflexes (ELCR, peak latency ~30–70 ms) in the stationary arm muscles are modulated during different types of rhythmic leg cycling63). The subjects performed leg pedaling (60 or 90 rpm) while simultane-ously contracting their arm muscles isometrically. Control experiments included isolated isometric contractions and discrete movements of the leg. ELCRs were evoked by stimulation of the superficial radial nerve with a train of rectangular pulses (3 pulses at 333 Hz, intensity at 2.0- to 2.5-fold perceptual threshold). Reflex amplitudes were significantly increased in the flexor carpi radialis and posterior deltoid and significantly decreased in the biceps brachii muscles during leg pedaling compared with that

Fig. 7 Summary of the kinematic changes at the ankle with superficial peroneal (SP, top) and superficial radial (SR, bottom) nerve stimulation at the stance-swing transition for both the ipsilateral (left) and contralateral (right) sides. Solid foot represents the foot in which the response to stimulus occurred. Jagged arrow indicates site of stimulation; solid arrow indicates plantar flex-ion; open arrow indicates dorsiflexion. Arrows indicate direction of dorsiflexion (DF) and plantar flexion (PF) for both SR and SP nerves. Adopted from Haridas et al.90).


during stationary isometric contraction of the lower leg muscles (Fig. 8). This effect was also sensitive to cadence. However, no significant modulation was observed dur-ing the rhythmic isometric contractions or discrete one-shot-like cyclic movements of the leg. Additionally, there was no phase-dependent modulation of the ELCR. These findings suggest that activation of the rhythm generating system of the legs selectively affects the excitability of the early latency cutaneous reflex pathways in the arm muscles. In addition, these findings further support the contribution of an interlimb interaction between the pre-sumed lower limb neural system and the neural circuit of the cutaneous reflex in the upper limbs6,8,21,94). This would result in an increase of the excitability of the circuitry for the cutaneous reflex (offset regulation)63).

Fig. 8 Top: schematic illustration of the experimental paradigm. A: typical recordings of the ELCR for the FCR (top traces) and PD (bottom traces) during leg pedaling at 60 rpm (thin lines), 90 rpm (thick lines), and stationary (dashed lines) from a single sub-ject. B: grand means and SDs of the ELCR during each task. C: upper traces show typical EMG recordings of the VL during pedaling of the right leg (ipsilateral side with respect to the electrical stimulation, top trace) and rhythmic isometric contraction of the right knee extensors (bottom trace). Bottom panels show grand means and SDs of the ELCR for the FCR (left) and PD (right) while performing ipsilateral pedaling (black boxes) and while performing rhythmic isometric contraction of the right knee extensors (gray boxes). D: schematic illustrations of the changes in crank position (top), typical EMG recordings of the VL (middle), and knee angle position (bottom) while performing a one-shot discrete leg movement. E: grand means and SDs of the ELCR for the FCR (left) and PD (right) while performing ipsilateral pedaling (black boxes) and while performing a discrete movement of the right knee (gray boxes). Adopted from Sasada et al.63).

SR nerve

C: VL EMG

Col 1 vs Col 2

Time (msec)-100 -50 0 50 100

0

5

10

15

0

2

4

6

8

VL EMG

Knee angle

40v

40deg

FCRPD

Disc IpsiStat Disc IpsiStatRef

lex

ampl

itude

(% E

MG

max

)

D En = 7

n =7

Leg cycling

SR nerve

C: VL EMG

Col 1 vs Col 2

Time (msec)-100 -50 0 50 100

0

5

10

15

0

2

4

6

8

VL EMG

Knee angle

40v

40deg

FCRPD


lex

ampl

itude

(% E

MG

max

)

D En = 7

n =7

Leg cycling

SR nerve

C: VL EMG

Col 1 vs Col 2

Time (msec)-100 -50 0 50 100

0

5

10

15

0

2

4

6

8

VL EMG

Knee angle

40v

40deg

FCRPD


lex

ampl

itude

(% E

MG

max

)

D En = 7

n =7

Leg cycling


References

1) Sherrington CS 1910. Flexion-reflex of the limb, crossed extension-reflex, and reflex stepping and standing. J Physiol 40: 28-121.

2) Sherrington CS, Laslett EE 1903. Observations on some spinal reflexes and the interconnection of spinal segments. J Physiol 29: 58-96.

3) Hagbarth KE 1952. Excitatory and inhibitory skin areas for flexor and extensor motoneurons. Acta Physiol Scand Suppl 26: 1-58.

4) Kugelberg E, Hagbarth KE 1958. Spinal mechanism of the abdominal and erector spinae skin reflexes. Brain 81: 290-304.

5) Schomburg ED, Roesler J, Meinck HM 1977. Phase-depen-dent transmission in the excitatory propriospinal reflex path-way from forelimb afferents to lumbar motoneurones during fictive locomotion. Neurosci Lett 4: 249-252.

6) Dietz V 2002. Do human bipeds use quadrupedal coordina-tion? Trends Neurosci 25: 462-467.

7) Dietz V, Duysens J 2000. Significance of load receptor input during locomotion: a review. Gait Posture 11: 102-110.

8) Zehr EP, Duysens J 2004. Regulation of arm and leg move-ment during human locomotion. Neuroscientist 10: 347-361.

9) Datta AK, Harrison LM, Stephens JA 1989. Task-dependent changes in the size of response to magnetic brain stimulation in human first dorsal interosseous muscle. J Physiol 418: 13-23.

10) Gibbs J, Harrison LM, Stephens JA, Evans AL 1999. Cuta-neomuscular reflex responses recorded from the lower limb in children and adolescents with cerebral palsy. Dev Med Child Neurol 41: 456-464.

11) Evans AL, Harrison LM, Stephens JA 1989. Task-dependent changes in cutaneous reflexes recorded from various muscles controlling finger movement in man. J Physiol 418: 1-12.

12) Jenner JR, Stephens JA 1982. Cutaneous reflex responses and their central nervous pathways studied in man. J Physiol 333: 405-419.

13) Evans AL, Harrison LM, Stephens JA 1990. Maturation of the cutaneomuscular reflex recorded from the first dorsal in-

terosseous muscle in man. J Physiol 428: 425-440.14) Van Wezel BM, Ottenhoff FA, Duysens J 1997. Dynamic

control of location-specific information in tactile cutaneous reflexes from the foot during human walking. J Neurosci 17: 3804-3814.

15) Zehr EP, Stein RB, Komiyama T 1998. Function of sural nerve reflexes during human walking. J Physiol 507 (Pt 1): 305-314.

16) Forssberg H, Grillner S, Rossignol S 1975. Phase dependent reflex reversal during walking in chronic spinal cats. Brain Res 85: 103-107.

17) Wand P, Prochazka A, Sontag KH 1980. Neuromuscular responses to gait perturbations in freely moving cats. Exp Brain Res 38: 109-114.

18) Miller S, Ruit JB, Van der Meche FG 1977. Reversal of sign of long spinal reflexes dependent on the phase of the step cycle in the high decerebrate cat. Brain Res 128: 447-459.

19) Miller S, Van Der Burg J, Van Der Meche F 1975. Locomo-tion in the cat: basic programmes of movement. Brain Res 91: 239-253.

20) Gibbs J, Harrison LM, Stephens JA 1995. Cutaneomuscular reflexes recorded from the lower limb in man during differ-ent tasks. J Physiol 487 (Pt 1): 237-242.

21) Zehr EP, Collins DF, Chua R 2001. Human interlimb reflexes evoked by electrical stimulation of cutaneous nerves inner-vating the hand and foot. Exp Brain Res 140: 495-504.

22) Burke D, Dickson HG, Skuse NF 1991. Task-dependent changes in the responses to low-threshold cutaneous afferent volleys in the human lower limb. J Physiol 432: 445-458.

23) Zehr EP, Komiyama T, Stein RB 1997. Cutaneous reflexes during human gait: electromyographic and kinematic re-sponses to electrical stimulation. J Neurophysiol 77: 3311-3325.

24) Yang JF, Stein RB 1990. Phase-dependent reflex reversal in human leg muscles during walking. J Neurophysiol 63: 1109-1117.

25) De Serres SJ, Yang JF, Patrick SK 1995. Mechanism for re-flex reversal during walking in human tibialis anterior mus-cle revealed by single motor unit recording. J Physiol 488 (Pt 1): 249-258.

26) Baken BC, Dietz V, Duysens J 2005. Phase-dependent mod-ulation of short latency cutaneous reflexes during walking in man. Brain Res 1031: 268-275.

27) Wannier T, Bastiaanse C, Colombo G, Dietz V 2001. Arm to leg coordination in humans during walking, creeping and swimming activities. Exp Brain Res 141: 375-379.

28) Duysens J, Tax AA, Nawijn S, Berger W, Prokop T, Alten-muller E 1995. Gating of sensation and evoked potentials following foot stimulation during human gait. Exp Brain Res 105: 423-431.

29) Zehr EP, Collins DF, Frigon A, Hoogenboom N 2003. Neu-ral control of rhythmic human arm movement: phase depen-dence and task modulation of hoffmann reflexes in forearm muscles. J Neurophysiol 89: 12-21.

30) Zehr EP, Kido A 2001. Neural control of rhythmic, cyclical human arm movement: task dependency, nerve specificity and phase modulation of cutaneous reflexes. J Physiol 537: 1033-1045.

31) Nakajima T, Sakamoto M, Endoh T, Komiyama T 2006. Lo-cation-specific and task-dependent modulation of cutaneous reflexes in intrinsic human hand muscles. Clin Neurophysiol

Conclusions

In this review, we discussed the unique gain regula-tion of cutaneous reflexes and H-reflex during locomotor movements in humans. Although there is some differ-ence in reflex regulation between bipeds and quadrupeds, there are many functional similarities of reflex responses between them. Many previous studies suggested that the CPG system plays a key role in differential regulation of cutaneous reflex and H-reflex gain during locomo-tor movements and stationary contraction. However, the minimum requirement of cycling frequency, rotation and load for driving CPG in humans remains unclear. These factors should be elucidated in future studies to apply arm and leg cycling as rehabilitation training for patients with gait disorders. Also, the developmental aspects of reflex regulation during locomotor movement are little known, and need to be explored in the future.


erators and quadrupedal locomotion in the neonatal rat. Eur J Neurosci 14: 1727-1738.

51) Juvin L, Simmers J, Morin D 2005. Propriospinal circuitry underlying interlimb coordination in mammalian quadrupe-dal locomotion. J Neurosci 25: 6025-6035.

52) Reed WR, Shum-Siu A, Onifer SM, Magnuson DS 2006. Inter-enlargement pathways in the ventrolateral funiculus of the adult rat spinal cord. Neuroscience 142: 1195-1207.

53) Juvin L, Simmers J, Morin D 2007. Locomotor rhythmo-genesis in the isolated rat spinal cord: a phase-coupled set of symmetrical flexion extension oscillators. J Physiol 583: 115-128.

54) Leblond H, Menard A, Gossard JP 2001. Corticospinal con-trol of locomotor pathways generating extensor activities in the cat. Exp Brain Res 138: 173-184.

55) Conway BA, Hultborn H, Kiehn O 1987. Proprioceptive in-put resets central locomotor rhythm in the spinal cat. Exp Brain Res 68: 643-656.

56) Rossignol S, Dubuc R, Gossard JP 2006. Dynamic senso-rimotor interactions in locomotion. Physiol Rev 86: 89-154.

57) Frigon A, Gossard JP 2010. Evidence for specialized rhythm-generating mechanisms in the adult mammalian spinal cord. J Neurosci 30: 7061-7071.

58) Duysens J, Pearson KG 1976. The role of cutaneous afferents from the distal hindlimb in the regulation of the step cycle of thalamic cats. Exp Brain Res 24: 245-255.

59) Guertin P, Angel MJ, Perreault MC, McCrea DA 1995. Ankle extensor group I afferents excite extensors throughout the hindlimb during fictive locomotion in the cat. J Physiol 487 (Pt 1): 197-209.

60) Burke RE 1999. The use of state-dependent modulation of spinal reflexes as a tool to investigate the organization of spi-nal interneurons. Exp Brain Res 128: 263-277.

61) Brooke JD, Cheng J, Collins DF, McIlroy WE, Misiaszek JE, Staines WR 1997. Sensori-sensory afferent conditioning with leg movement: gain control in spinal reflex and ascend-ing paths. Prog Neurobiol 51: 393-421.

62) Zehr EP, Balter JE, Ferris DP, Hundza SR, Loadman PM, Stoloff RH 2007. Neural regulation of rhythmic arm and leg movement is conserved across human locomotor tasks. J Physiol 582: 209-227.

63) Sasada S, Tazoe T, Nakajima T, Zehr EP, Komiyama T 2009. Effects of leg pedaling on early latency cutaneous reflexes in upper limb muscles. J Neurophysiol 104: 210-217.

64) Matthews PB 1986. Observations on the automatic compen-sation of reflex gain on varying the pre-existing level of mo-tor discharge in man. J Physiol 374: 73-90.

65) Brooke JD, McIlroy WE, Collins DF 1992. Movement fea-tures and H-reflex modulation. I. Pedalling versus matched controls. Brain Res 582: 78-84.

66) McIlroy WE, Collins DF, Brooke JD 1992. Movement fea-tures and H-reflex modulation. II. Passive rotation, move-ment velocity and single leg movement. Brain Res 582: 85-93.

67) Collins DF, McIlroy WE, Brooke JD 1993. Contralateral in-hibition of soleus H reflexes with different velocities of pas-sive movement of the opposite leg. Brain Res 603: 96-101.

68) Mileva K, Green DA, Turner DL 2004. Neuromuscular and biomechanical coupling in human cycling: modulation of cutaneous reflex responses to sural nerve stimulation. Exp Brain Res 158: 450-464.

117: 420-429.32) Nakajima T, Sakamoto M, Tazoe T, Endoh T, Komiyama T

2009. Location-specific modulations of plantar cutaneous re-flexes in human (peroneus longus muscle) are dependent on co-activation of ankle muscles. Exp Brain Res 195: 403-412.

33) Nakajima T, Sakamoto M, Tazoe T, Endoh T, Komiyama T 2006. Location specificity of plantar cutaneous reflexes in-volving lower limb muscles in humans. Exp Brain Res 175: 514-525.

34) Drew T, Rossignol S 1987. A kinematic and electromyo-graphic study of cutaneous reflexes evoked from the fore-limb of unrestrained walking cats. J Neurophysiol 57: 1160-1184.

35) Duysens J 1977. Reflex control of locomotion as revealed by stimulation of cutaneous afferents in spontaneously walking premammillary cats. J Neurophysiol 40: 737-751.

36) Barriere G, Leblond H, Provencher J, Rossignol S 2008. Prominent role of the spinal central pattern generator in the recovery of locomotion after partial spinal cord injuries. J Neurosci 28: 3976-3987.

37) Grillner S 1975. Locomotion in vertebrates: central mecha-nisms and reflex interaction. Physiol Rev 55: 247-304.

38) Grillner S, Dubuc R 1988. Control of locomotion in verte-brates: spinal and supraspinal mechanisms. Adv Neurol 47: 425-453.

39) Duysens J, Van de Crommert HW 1998. Neural control of lo-comotion; The central pattern generator from cats to humans. Gait Posture 7: 131-141.

40) Van de Crommert HW, Mulder T, Duysens J 1998. Neural control of locomotion: sensory control of the central pattern generator and its relation to treadmill training. Gait Posture 7: 251-263.

41) Brown TG 1914. On the nature of the fundamental activity of the nervous centres; together with an analysis of the con-ditioning of rhythmic activity in progression, and a theory of the evolution of function in the nervous system. J Physiol 48: 18-46.

42) Kiehn O 2006. Locomotor circuits in the mammalian spinal cord. Annu Rev Neurosci 29: 279-306.

43) McCrea DA, Rybak IA 2008. Organization of mammalian locomotor rhythm and pattern generation. Brain Res Rev 57: 134-146.

44) Rossignol S, Frigon A 2011. Recovery of locomotion after spinal cord injury: some facts and mechanisms. Annu Rev Neurosci 34: 413-440.

45) Grillner S, Zangger P 1979. On the central generation of lo-comotion in the low spinal cat. Exp Brain Res 34: 241-261.

46) Marcoux J, Rossignol S 2000. Initiating or blocking loco-motion in spinal cats by applying noradrenergic drugs to re-stricted lumbar spinal segments. J Neurosci 20: 8577-8585.

47) Langlet C, Leblond H, Rossignol S 2005. Mid-lumbar seg-ments are needed for the expression of locomotion in chronic spinal cats. J Neurophysiol 93: 2474-2488.

48) Delivet-Mongrain H, Leblond H, Rossignol S 2008. Effects of localized intraspinal injections of a noradrenergic blocker on locomotion of high decerebrate cats. J Neurophysiol 100: 907-921.

49) Cazalets JR, Borde M, Clarac F 1995. Localization and or-ganization of the central pattern generator for hindlimb loco-motion in newborn rat. J Neurosci 15: 4943-4951.

50) Ballion B, Morin D, Viala D 2001. Forelimb locomotor gen-


69) Zehr EP, Hesketh KL, Chua R 2001. Differential regulation of cutaneous and H-reflexes during leg cycling in humans. J Neurophysiol 85: 1178-1184.

70) Frigon A, Collins DF, Zehr EP 2004. Effect of rhythmic arm movement on reflexes in the legs: modulation of soleus H-reflexes and somatosensory conditioning. J Neurophysiol 91: 1516-1523.

71) Alstermark B, Isa T, Pettersson LG, Sasaki S 2007. The C3-C4 propriospinal system in the cat and monkey: a spinal pre-motoneuronal centre for voluntary motor control. Acta Physiol (Oxf) 189: 123-140.

72) Barthelemy D, Nielsen JB Corticospinal contribution to arm muscle activity during human walking. J Physiol 588: 967-979.

73) Elftman H 1938. The Measurement of the External Force in Walking. Science 88: 152-153.

74) Ballesteros ML, Buchthal F, Rosenfalck P 1965. The Pattern of Muscular Activity during the Arm Swing of Natural Walk-ing. Acta Physiol Scand 63: 296-310.

75) Zehr EP, Carroll TJ, Chua R, Collins DF, Frigon A, Haridas C, Hundza SR, Thompson AK 2004. Possible contributions of CPG activity to the control of rhythmic human arm move-ment. Can J Physiol Pharmacol 82: 556-568.

76) Balter JE, Zehr EP 2007. Neural coupling between the arms and legs during rhythmic locomotor-like cycling movement. J Neurophysiol 97: 1809-1818.

77) Zehr EP, Hundza SR, Vasudevan EV 2009. The quadrupedal nature of human bipedal locomotion. Exerc Sport Sci Rev 37: 102-108.

78) Yamaguchi T 2004. The central pattern generator for fore-limb locomotion in the cat. Prog Brain Res 143: 115-122.

79) Zehr EP, Chua R 2000. Modulation of human cutaneous re-flexes during rhythmic cyclical arm movement. Exp Brain Res 135: 241-250.

80) Komiyama T, Zehr EP, Stein RB 2000. Absence of nerve specificity in human cutaneous reflexes during standing. Exp Brain Res 133: 267-272.

81) Carroll TJ, Zehr EP, Collins DF 2005. Modulation of cutane-ous reflexes in human upper limb muscles during arm cy-cling is independent of activity in the contralateral arm. Exp Brain Res 161: 133-144.

82) Vasudevan EV, Zehr EP 2011. Multi-frequency arm cycling reveals bilateral locomotor coupling to increase movement

symmetry. Exp Brain Res 211: 299-312.83) Duysens J, Trippel M, Horstmann GA, Dietz V 1990. Gat-

ing and reversal of reflexes in ankle muscles during human walking. Exp Brain Res 82: 351-358.

84) Matsuyama K, Nakajima K, Mori F, Aoki M, Mori S 2004. Lumbar commissural interneurons with reticulospinal inputs in the cat: morphology and discharge patterns during fictive locomotion. J Comp Neurol 474: 546-561.

85) Zehr EP, Haridas C 2003. Modulation of cutaneous reflexes in arm muscles during walking: further evidence of similar control mechanisms for rhythmic human arm and leg move-ments. Exp Brain Res 149: 260-266.

86) Zehr EP, Hundza SR 2005. Forward and backward arm cy-cling are regulated by equivalent neural mechanisms. J Neu-rophysiol 93: 633-640.

87) Zehr EP, Stein RB 1999. What functions do reflexes serve during human locomotion? Prog Neurobiol 58: 185-205.

88) Haridas C, Zehr EP, Misiaszek JE 2005. Postural uncertainty leads to dynamic control of cutaneous reflexes from the foot during human walking. Brain Res 1062: 48-62.

89) Dietz V, Fouad K, Bastiaanse CM 2001. Neuronal coordina-tion of arm and leg movements during human locomotion. Eur J Neurosci 14: 1906-1914.

90) Haridas C, Zehr EP 2003. Coordinated interlimb compensa-tory responses to electrical stimulation of cutaneous nerves in the hand and foot during walking. J Neurophysiol 90: 2850-2861.

91) Huang HJ, Ferris DP 2004. Neural coupling between upper and lower limbs during recumbent stepping. J Appl Physiol 97: 1299-1308.

92) Sakamoto M, Endoh T, Nakajima T, Tazoe T, Shiozawa S, Komiyama T 2006. Modulations of interlimb and intralimb cutaneous reflexes during simultaneous arm and leg cycling in humans. Clin Neurophysiol 117: 1301-1311.

93) Sakamoto M, Tazoe T, Nakajima T, Endoh T, Shiozawa S, Komiyama T 2007. Voluntary changes in leg cadence modu-late arm cadence during simultaneous arm and leg cycling. Exp Brain Res 176: 188-192.

94) Haridas C, Zehr EP, Misiaszek JE 2006. Context-dependent modulation of interlimb cutaneous reflexes in arm muscles as a function of stability threat during walking. J Neuro-physiol 96: 3096-3103.

reflex modulation during rhythmic limb movements in humans

Documents