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Locomotion is produced by a central pattern generator. Its spinal cord organization is generally considered to be distributed, with more rhythmogenic rostral lumbar segments. While this produces a rostrocaudally traveling wave in undulating species, this is not thought to occur in limbed vertebrates, with the exception of the interneuronal traveling wave demonstrated in fictive cat scratching (Cuellar et al. J Neurosci 29:798-810, 2009). Here, we reexamine this hypothesis in the frog, using the seven muscle synergies A to G previously identified with intraspinal NMDA (Saltiel et al. J Neurophysiol 85:605-619, 2001). We find that locomotion consists of a sequence of synergy activations (A-B-G-A-F-E-G). The same sequence is observed when focal NMDA iontophoresis in the spinal cord elicits a caudal extension-lateral force-flexion cycle (flexion onset without the C synergy). Examining the early NMDA-evoked motor output at 110 sites reveals a rostrocaudal topographic organization of synergy encoding by the lumbar cord. Each synergy is preferentially activated from distinct regions, which may be multiple, and partially overlap between different synergies. Comparing the sequence of synergy activation in locomotion with their spinal cord topography suggests that the locomotor output is achieved by a rostrocaudally traveling wave of activation in the swing-stance cycle. A two-layer circuitry model, based on this topography and a traveling wave reproduces this output and explores its possible modifications under different afferent inputs. Our results and simulations suggest that a rostrocaudally traveling wave of excitation takes advantage of the topography of interneuronal regions encoding synergies, to activate them in the proper sequence for locomotion.

Motor modules are neural entities hypothesized to be building blocks of movement construction. How motor modules are underpinned by neural circuits has remained obscured. As a first step towards dissecting these circuits, we optogenetically evoked motor outputs from the lumbosacral spinal cord of two strains of transgenic mice - the Chat, with channelrhodopsin (ChR2) expressed in motoneurons, and the Thy1, expressed in putatively excitatory neurons. Motor output was represented as a spatial field of isometric ankle force. We found that Thy1 force fields were more complex and diverse in structure than Chat fields: the Thy1 fields comprised mostly non-parallel vectors while the Chat fields, mostly parallel vectors. In both, most fields elicited by co-stimulation of two laser beams were well explained by linear combination of the separately-evoked fields. We interpreted the Thy1 force fields as representations of spinal motor modules. Our comparison of the Chat and Thy1 fields allowed us to conclude, with reasonable certainty, that the structure of neuromotor modules originates from excitatory spinal interneurons. Our results not only demonstrate, for the first time using optogenetics, how the spinal modules follow linearity in their combinations, but also provide a reference against which future optogenetic studies of modularity can be compared.

Inhibitory neurons in the adult mammalian spinal cord are known to locally modulate afferent feedback--from muscle proprioceptors and from skin receptors--to pattern motor activity for locomotion and postural control. Here, using optogenetic tools, we explored how the same population of inhibitory interneurons globally affects hindlimb movements in the spinal cord of both anesthetized and freely moving mice. Activation of inhibitory interneurons up to the middle/lower spinal cord i.e. T8-T9, were able to completely and globally suppress all ipsilateral hindlimb movements. Furthermore, the same population of interneurons--which inhibited movements--did not significantly change the sensory and proprioceptive information from the affected limbs to the cortex. These results suggest a rostro-caudal organization of inhibition in the spinal cord motor output without modulation of ascending sensory pathways.

Previous studies using intact and spinalized animals have suggested that coordinated movements can be generated by appropriate combinations of muscle synergies controlled by the central nervous system (CNS). However, which CNS regions are responsible for expressing muscle synergies remains an open question. We address whether the brain stem and spinal cord are involved in expressing muscle synergies used for executing a range of natural movements. We analyzed the electromyographic (EMG) data recorded from frog leg muscles before and after transection at different levels of the neuraxis-rostral midbrain (brain stem preparations), rostral medulla (medullary preparations), and the spinal-medullary junction (spinal preparations). Brain stem frogs could jump, swim, kick, and step, while medullary frogs could perform only a partial repertoire of movements. In spinal frogs, cutaneous reflexes could be elicited. Systematic EMG analysis found two different synergy types: 1) synergies shared between pre- and posttransection states and 2) synergies specific to individual states. Almost all synergies found in natural movements persisted after transection at rostral midbrain or medulla but not at the spinal-medullary junction for swim and step. Some pretransection- and posttransection-specific synergies for a certain behavior appeared as shared synergies for other motor behaviors of the same animal. These results suggest that the medulla and spinal cord are sufficient for the expression of most muscle synergies in frog behaviors. Overall, this study provides further evidence supporting the idea that motor behaviors may be constructed by muscle synergies organized within the brain stem and spinal cord and activated by descending commands from supraspinal areas.

We review experiments supporting the hypothesis that the vertebrate motor system produces movements by combining a small number of units of motor output. Using a variety of approaches such as microstimulation of the spinal cord, NMDA iontophoresis, and an examination of natural behaviors in intact and deafferented animals we have provided evidence for a modular organization of the spinal cord. A module is a functional unit in the spinal cord that generates a specific motor output by imposing a specific pattern of muscle activation. Such an organization might help to simplify the production of movements by reducing the degrees of freedom that need to be specified.

We have previously reported that focal intraspinal N-methyl-d-aspartate (NMDA) iontophoresis in the frog elicits a motor output, which is organized in terms of its constituent isometric force directions at the ipsilateral ankle and its topography. Furthermore, the associated EMG patterns can be reconstructed as the linear combinations of seven muscle synergies, labeled A to G. We now focus on one of the most common NMDA-elicited outputs, the adduction-caudal extension-flexion rhythm, and examine the relationship between the different force phases in terms of synergies and topography. Two distinct EMG patterns produce caudal extensions, and only one of the two patterns is used at most sites. The key synergy combinations for the two patterns are B + e and D + c (strongest synergies capitalized). These two patterns map at distinct locations in the lumbar cord. Within individual sites rhythms, we find linkages among the synergies used to produce adductions, the onsets of flexions after caudal extensions, and the synergy pattern producing the caudal extensions. For example, the synergy composition of adductions at B + e caudal extension sites is dominated by E + b and at D + c caudal extension sites by C + d. The two types of adductions map at distinct locations, situated between the two caudal extension regions. Specifically the linked patterns of caudal extension-adduction interleave rostrocaudally in a CE2-ADD1-ADD2-CE1 sequence, where 1 and 2 refer to the two pattern types. The implications of this topography and connectivity with respect to motor systems organization and behaviors are discussed.

Previous studies have suggested that the motor system may simplify control by combining a small number of muscle synergies represented as activation profiles across a set of muscles. The role of sensory feedback in the activation and organization of synergies has remained an open question. Here, we assess to what extent the motor system relies on centrally organized synergies activated by spinal and/or supraspinal commands to generate motor outputs by analyzing electromyographic (EMG) signals collected from 13 hindlimb muscles of the bullfrog during swimming and jumping, before and after deafferentation. We first established that, for both behaviors, the intact and deafferented data sets possess low and similar dimensionalities. Subsequently, we used a novel reformulation of the non-negative matrix factorization algorithm to simultaneously search for synergies shared by, and synergies specific to, the intact and deafferented data sets. Most muscle synergies were identified as shared synergies, suggesting that EMGs of locomotor behaviors are generated primarily by centrally organized synergies. Both the amplitude and temporal patterns of the activation coefficients of most shared synergies, however, were altered by deafferentation, suggesting that sensory inflow modulates activation of those centrally organized synergies. For most synergies, effects of deafferentation on the activation coefficients were not consistent across frogs, indicating substantial interanimal variability of feedback actions. We speculate that sensory feedback might adapt recruitment of muscle synergies to behavioral constraints, and the few synergies specific to the intact or deafferented states might represent afferent-specific modules or feedback reorganization of spinal neuronal networks.

The vertebrate nervous system produces a wide range of movement flexibly and efficiently, even though the simplest of these movements is potentially highly complex. The strategies by which the nervous system overcomes these complexities have therefore been of interest to motor physiologists for decades. In this review, the authors present a number of recent experiments that propose one strategy by which the nervous system might simplify the production of movement. These experiments suggest that spinal motor systems are organized in terms of a small number of distinct motor responses, or "modules." These distinct modules can be combined together simply to produce a wide range of different movements. Such a modular organization of spinal motor systems can potentially allow the nervous system to produce a wide range of natural behaviors in a simple and flexible manner.

We review here experiments examining the hypothesis that vertebrate spinal motor systems produce movement through the flexible combination of a small number of units of motor output. Using a variety of preparations and techniques, these experiments provide evidence for such spinally generated units and for the localization of the networks responsible for producing them within different regions of the spinal cord. Such an organization might help to simplify the production of movement, reducing the degrees of freedom that need to be specified by providing a set of units involved in regulating features common to a range of behaviors.

The ability to produce various force patterns at the ankle by microstimulation of the gray matter of the spinal cord was investigated in spinalized frogs. We evaluated the recruitment properties of individual spinal sites and found that forces increase linearly with activation level in the low-force range studied, while the structure of the force pattern remains invariant. We also measured the responses produced by coactivation of two spinal sites activated at two pairs of stimulation levels. Responses were measured at the mechanical level by recording forces at the ankle; and, at the muscular level by recording the electromyographic (EMG) activity of 11 hindlimb muscles. We found that for both pairs of activation, the forces under coactivation were the scaled vectorial summation of the individual responses. At the muscular level, rectified and integrated EMGs also summated during coactivation. Numerous force patterns could, thus, be created by the activation of a few individual sites. These results suggest that microstimulation of the circuitry of the spinal cord (higher order neurons than the motoneurons) holds promise as a new functional neuromuscular stimulation (FNS) technique for the restoration of multi-joint movements.

This paper relates to the problem of the existence of muscle synergies, that is whether the CNS command to muscles is simplified by controlling their activity in subgroups or synergies, rather than individually. We approach this problem with two methods that have been recently introduced: intraspinal N-methyl-D-aspartate (NMDA) microstimulation and a synergy-extracting algorithm. To search for a common set of synergies encoded for by the spinal cord whose combinations would account for a large range of electromyographic (EMG) patterns, we chose, rather than examining a large range of natural behaviors, to chemically microstimulate a large number of spinal cord interneuronal sites in different frogs. A possible advantage of this complementary method is that it is task-independent. Visual inspection suggested that the NMDA-elicited EMG patterns recorded from 12 leg muscles might indeed be constructed from smaller subgroups of muscles whose activity co-varied, suggestive of synergies. We used a modification of our extracting computational algorithm whereby a nonnegative least-squares method was employed to iteratively update both the synergies and their coefficients of activation in reconstructing the EMG patterns. Using this algorithm, a limited set of seven synergies was found whose linear combinations accounted for more than 91% of the variance in the pooled EMG data from 10 frogs, and more than 96% in individual frogs. The extracted synergies were similar among frogs. Further, preferred combinations of these synergies were clearly identified. This was found by extracting smaller sets of four, five, or six synergies and fitting each synergy from those sets as a combination from the set of seven synergies extracted from the same frog; the synergy combinations from each frog were then pooled together to examine their frequency of occurrence. Concordance with this method of identifying synergy combinations was found by examining how the synergies from the set of seven correlated pair-wise as they reconstructed the EMG data. These results support the existence of muscle synergies encoded within the spinal cord, which through preferred combinations, account for a large repertoire of spinal cord motor output. These findings are contrasted with previous approaches to the problem of synergies.

The production and control of complex motor functions are usually attributed to central brain structures such as cortex, basal ganglia and cerebellum. In traditional schemes the spinal cord is assigned a subservient function during the production of movement, playing a predominantly passive role by relaying the commands dictated to it by supraspinal systems. This review challenges this idea by presenting evidence that the spinal motor system is an active participant in several aspects of the production of movement, contributing to functions normally ascribed to 'higher' brain regions.

We describe the responses evoked by microstimulation of interneuronal regions of the spinal cord in unanesthetized rats chronically spinalized at T10-T12. One to three weeks after spinalization, sites in the lumbar spinal cord were stimulated using trains of low current microstimulation. The isometric force produced by stimulation of a spinal site was measured at the ankle. Responses were reliably observed from stimulation of a region within the first 1250 microm from the dorsal surface of the spinal cord. These responses were clearly not due to direct motoneuronal activation and were maintained after chronic deafferentation. The force evoked by microstimulation and measured at the ankle varied smoothly across the workspace. Simultaneous stimulation of two sites in the spinal cord produced a response that was a simple linear summation of the responses evoked from each of the sites alone. Microstimulation generally produced a highly non-uniform distribution of response directions, biased toward responses which pulled the limb toward the body. Within these distributions there appeared to be two main types of responses. These different types of responses were preferentially evoked by microstimulation of different rostrocaudal regions of the spinal cord. This anatomical organization paralleled the spinal cutaneous somatotopy, as assessed by recording cutaneous receptive fields of neurons at sites to which the microstimulation was applied. This relationship was maintained after chronic deafferentation. The findings described here in the rat spinal cord in large part replicate those previously described in the frog.

We used a computational analysis to identify the basic elements with which the vertebrate spinal cord constructs one complex behavior. This analysis extracted a small set of muscle synergies from the range of muscle activations generated by cutaneous stimulation of the frog hindlimb. The flexible combination of these synergies was able to account for the large number of different motor patterns produced by different animals. These results therefore demonstrate one strategy used by the vertebrate nervous system to produce movement in a computationally simple manner.

Previous work using electrical microstimulation has suggested the existence of modules subserving limb posture in the spinal cord. In this study, the question of modular organization was reinvestigated with the more selective method of chemical microstimulation. N-methyl--aspartate (NMDA) iontophoresis was applied to 229 sites of the lumbar spinal cord gray while monitoring the isometric force output of the ipsilateral hindlimb at the ankle. A force response was elicited from 69 sites. At 18 of these sites, tonic forces were generated and rhythmic forces at 44. In the case of tonic forces, their directions clustered along four orientations: lateral extension, rostral flexion, adduction, and caudal extension. For the entire set of forces (tonic and rhythmic), the same clusters of orientations were found with the addition of a cluster directed as a flexion toward the body. This distribution of force orientations was quite comparable to that obtained with electrical stimulation at the same sites. The map of tonic responses revealed a topographic organization; each type of force orientation was elicited from sites that grouped together in zones at distinct rostrocaudal and depth locations. In the case of rhythmic sequences of force orientations, some were distinctly more common, whereas others were rarely elicited by NMDA. Mapping of the most common rhythms showed that each was elicited from two or three regions of the cord. These regions were close in location to the tonic regions that produced those forces that represented components specific to that rhythm. There was an additional caudal region from which the different rhythms also could be elicited. Taken together, these results support the concept of a modular organization of the motor system in the frog's spinal cord and delineate the topography of these modules. They also suggest that these modules are used by the circuitry underlying rhythmic pattern generation by the spinal cord.

The issue of translating the planning of arm movements into muscle forces is discussed in relation to the recent discovery of structures in the spinal cord. These structures contain circuitry that, when activated, produce precisely balanced contractions in groups of muscles. These synergistic contractions generate forces that direct the limb toward an equilibrium point in space. Remarkably, the force outputs, produced by activating different spinal-cord structures, sum vectorially. This vectorial combination of motor outputs might be a mechanism for producing a vast repertoire of motor behaviors in a simple manner.

Recent experiments using electrical and N-methyl-D-aspartate microstimulation of the spinal cord gray matter and cutaneous stimulation of the hindlimb of spinalized frogs have provided evidence for a modular organization of the frog's spinal cord circuitry. A "module" is a functional unit in the spinal cord circuitry that generates a specific motor output by imposing a specific pattern of muscle activation. The output of a module can be characterized as a force field: the collection of the isometric forces generated at the ankle over different locations in the leg's workspace. Different modules can be combined independently so that their force fields linearly sum. The goal of this study was to ascertain whether the force fields generated by the activation of supraspinal structures could result from combinations of a small number of modules. We recorded a set of force fields generated by the electrical stimulation of the vestibular nerve in seven frogs, and we performed a principal component analysis to study the dimensionality of this set. We found that 94% of the total variation of the data is explained by the first five principal components, a result that indicates that the dimensionality of the set of fields evoked by vestibular stimulation is low. This result is compatible with the hypothesis that vestibular fields are generated by combinations of a small number of spinal modules.

The complex issue of translating the planning of arm movements into muscle forces is discussed in relation to the recent discovery of structures in the spinal cord. These structures contain circuitry that, when activated, produce precisely balanced contractions in groups of muscles. These synergistic contractions generate forces that direct the limb toward an equilibrium point in space. Remarkably, the force outputs, produced by activating different spinal-cord structures, sum vectorially. This vectorial combination of motor outputs might be a mechanism for producing a vast repertoire of motor behaviors in a simple manner.

Recent investigations on the spinalized frog have provided evidence suggesting that the neural circuits in the spinal cord are organized into a number of distinct functional modules. We have investigated the rule that governs the coactivation of two such modules. To this end, we have developed an experimental paradigm that involves the simultaneous stimulation of two sites in the frog's spinal cord and the quantitative comparison of the resulting mechanical response with the summation of the responses obtained from the stimulation of each site. We found that the simultaneous stimulation of two sites leads to the vector summation of the endpoint forces generated by each site separately. This linear behavior is quite remarkable and provides strong support to the view that the central nervous system may generate a wide repertoire of motor behaviors through the vectorial superposition of a few motor primitives stored within the neural circuits in the spinal cord.

Microstimulation of the gray matter of the frog's spinal cord was used to elicit motor responses. Force responses were recorded with the frog's ankle clamped while EMG activity was monitored. The collections of force patterns elicited at different leg configurations were summarized as force fields. These force fields showed convergence to an equilibrium point. The equilibrium paths were calculated from the force fields with the leg clamped. These paths predicted free limb motion in 75% of trials. The force fields were separated into active and prestimulation resting responses. The active force field responses had a fixed position equilibrium. These active force fields were modulated in amplitude over time, although the balance and orientations of forces in the pattern remained fixed. The active fields grouped into a few classes. These included both convergent and parallel fields. The convergent force fields (CFFS) could be observed in deafferented preparations. Motoneuron (MN) activity underlying the force fields was marked using sulforhodamine. The marked activity covered several segments. Several simulations and MN stimulations show that topography, limb geometry, and random activation could not account for the results. It is likely that propriospinal interneurons distribute the activity that underlies the responses observed here. Experiments showed that CFFs that resemble those elicited by microstimulation also underlie natural behaviors. The full variety of fields revealed by microstimulation was larger than the repertoire elicited by cutaneous stimulation. It was concluded that fixed-pattern force fields elicited in the spinal cord may be viewed as movement primitives. These force fields could form building blocks for more complex behaviors.

Spinalized frogs were microstimulated in the intermediate grey layers of the lumbar spinal cord; the forces evoked in the hindlimb were measured at several limb positions. The data were expressed as force fields. After the collection of many force fields, the dorsal roots were cut with the stimulating electrode in place, and the position-dependent stimulation-evoked forces were again measured repeatedly. We found that the position-dependent pattern of evoked forces--the force fields--did not change after the dorsal roots were cut. In other words, the postcut evoked forces pointed in the same direction as the precut evoked forces. This result was predicted and confirmed by the muscle activations (EMGs): Before and after the dorsal roots were cut, the same muscles were activated in the same proportions. In all limb positions, the rank ordering of the muscle activations remained fixed. The stimulation needed to evoke forces was increased by deafferentation, and there were subtle changes in the force magnitudes that were consistent with a linearization of the muscle stiffness by the afferents. We conclude that the microstimulation activated specific muscle synergies that resulted in limb forces pointing toward a particular posture. The patterns of evoked forces were predominantly attributable to feedforward activation of these muscle synergies.