Spinal cord pattern generators for locomotion.

Neuromodulatory Selection of Motor Neuron Recruitment Patterns in a Visuomotor Behavior Increases Speed.

Central patterns generators (CPGs) are neural circuits that drive rhythmic motor output without sensory feedback. Vertebrate CPGs are generally believed to operate in a top-down manner in which premotor interneurons activate motor neurons that in turn drive muscles. In contrast, the frog (Xenopus laevis) vocal CPG contains a functionally unexplored neuronal projection from the motor nucleus to the premotor nucleus, indicating a recurrent pathway that may contribute to rhythm generation. In this study, we characterized the function of this bottom-up connection. The X. laevis vocal CPG produces a 50-60 Hz "fast trill" song used by males during courtship. We recorded "fictive vocalizations" in the in vitro CPG from the laryngeal nerve while simultaneously recording premotor activity at the population and single-cell level. We show that transecting the motor-to-premotor projection eliminated the characteristic firing rate of premotor neurons. Silencing motor neurons with the intracellular sodium channel blocker QX-314 also disrupted premotor rhythms, as did blockade of nicotinic synapses in the motor nucleus (the putative location of motor neuron-to-interneuron connections). Electrically stimulating the laryngeal nerve elicited primarily IPSPs in premotor neurons that could be blocked by a nicotinic receptor antagonist. Our results indicate that an inhibitory signal, activated by motor neurons, is required for proper CPG function. To our knowledge, these findings represent the first example of a CPG in which precise premotor rhythms are tuned by motor neuron activity.SIGNIFICANCE STATEMENT Central pattern generators (CPGs) are neural circuits that produce rhythmic behaviors. In vertebrates, motor neurons are not commonly known to contribute to CPG function, with the exception of a few spinal circuits where the functional significance of motor neuron feedback is still poorly understood. The frog hindbrain vocal circuit contains a previously unexplored connection from the motor to premotor region. Our results indicate that motor neurons activate this bottom-up connection, and blocking this signal eliminates normal premotor activity. These findings may promote increased awareness of potential involvement of motor neurons in a wider range of CPGs, perhaps clarifying our understanding of network principles underlying motor behaviors in numerous organisms, including humans.

In this paper, we present an extended mathematical model of the central pattern generator (CPG) in the spinal cord. The proposed CPG model is used as the underlying low-level controller of a humanoid robot to generate various walking patterns. Such biological mechanisms have been demonstrated to be robust in locomotion of animal. Our model is supported by two neurophysiological studies. The first study identified a neural circuitry consisting of a two-layered CPG, in which pattern formation and rhythm generation are produced at different levels. The second study focused on a specific neural model that can generate different patterns, including oscillation. This neural model was employed in the pattern generation layer of our CPG, which enables it to produce different motion patterns-rhythmic as well as non-rhythmic motions. Due to the pattern-formation layer, the CPG is able to produce behaviors related to the dominating rhythm (extension/flexion) and rhythm deletion without rhythm resetting. The proposed multi-layered multi-pattern CPG model (MLMP-CPG) has been deployed in a 3D humanoid robot (NAO) while it performs locomotion tasks. The effectiveness of our model is demonstrated in simulations and through experimental results.

The role of the human spinal cord in complex processing of sensory information during locomotion has traditionally been thought to be minimal compared to other mammals. However, the evidence from experimental models of animals after spinal transection demonstrates that the spinal cord of at least some adult mammals can execute full weight bearing stepping independent of brain input. The interaction of sensory information derived from the moving limbs with central pattern generators in the spinal cord have been identified as important components of the neural control of locomotion. Some of the features of central pattern generation important for successful locomotion in animals include recognition of order of neural events, interpretation of patterns of sensory input in a state-dependent manner, and the availability of multiple neural circuits for successful stepping. If the human has similar potential to generate locomotion based on circuits within the spinal cord, then taking advantage of these mechanisms may enhance locomotor recovery after spinal cord injury (SCI). Recent evidence suggests that the human lumbosacral spinal cord can process complex sensory information during locomotion in the absence of detectable supraspinal influence. Also, activity-dependent plasticity is evident in spinal neural networks involved in the generation of stepping in humans. Locomotor training, a new approach to gait rehabilitation, is based on providing specific sensory information related to locomotion and repetitive practice usually on a treadmill with body weight support and manual assistance if needed. This approach takes advantage of the plasticity and motor learning capacity of the human spinal cord. Functional recovery of walking after SCI may be significantly improved by implementing locomotor training in new rehabilitative strategies that focus on enhancing recovery below the level of lesion.

In several vertebrates, stable rhythmic locomotor activity can be obtained from neural networks in the spinal cord without external periodic forcing. In an active animal, the spinal central pattern generator (CPG) is dynamically affected by descending input from the brain as well as afferent sensory inputs.1 While certain aspects of spinal CPG mechanisms for locomotor control have been well investigated, 3,8 the interactions of the CPG with the descending supraspinal inputs and sensory inputs are not well understood. Changes in the topology of the system caused by modifying the supraspinal-spinal CPG interactions are likely to influence the response of the system to external perturbations.

Tail nerve electrical stimulation promoted the efficiency of transplanted spinal cord-like tissue as a neuronal relay to repair the motor function of rats with transected spinal cord injury

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.

The aim of this report is not to make a differential diagnosis between epileptic nocturnal seizures and non-epileptic sleep-related movement disorders, or parasomnias. On the contrary, our goal is to emphasize the commonly shared semiological features of some epileptic seizures and parasomnias. Such similar features might be explained by the activation of the same neuronal networks (so-called ‘central pattern generators’ or CPG). These produce the stereotypical rhythmic motor sequences – in other words, behaviours – that are adaptive and species-specific (such as eating/alimentary, attractive/aversive, locomotor and nesting habits). CPG are located at the subcortical level (mainly in the brain stem and spinal cord) and, in humans, are under the control of the phylogenetically more recent neomammalian neocortical structures, according to a simplified Jacksonian model. Based on video-polygraphic recordings of sleep-related epileptic seizures and non-epileptic events (parasomnias), we have documented how a transient “neomammalian brain” dysfunction – whether epileptic or not – can ‘release’ (disinhibition?) the CPG responsible for involuntary motor behaviours. Thus, in both epileptic seizures and parasomnias, we can observe: (a) oroalimentary automatisms, bruxism and biting; (b) ambulatory behaviours, ranging from the classical bimanual–bipedal activity of ‘frontal’ hypermotor seizures, epileptic and non-epileptic wanderings, and somnambulism to periodic leg movements (PLM), alternating leg muscle activation (ALMA) and restless legs syndrome (RLS); and (c) various sleep-related events such as ictal fear, sleep terrors, nightmares and violent behaviour.

The effective production of many motor behaviors requires the strict coordination of discrete motor pattern generating circuits ([Hill et al. 2003][1]). Locomotor behaviors usually require this coordination at several levels of the nervous system, within single limbs (interjoint coordination),

Rhythmic motor behaviors in all animals appear to be under the control of "central pattern generator" circuits, neural circuits which can produce output patterns appropriate for behavior even when isolated from their normal peripheral inputs. Insects have been a useful model system in which to study the control of legged terrestrial locomotion. Much is known about walking in insects at the behavioral level, but to date there has been no clear demonstration that a central pattern generator for walking exists. The focus of this thesis is to explore the central neural basis for locomotion in the locust, Schistocerca americana. Rhythmic motor patterns could be evoked in leg motor neurons of isolated thoracic ganglia of locusts by the muscarinic agonist pilocarpine. These motor patterns would be appropriate for the movement of single legs during walking. Rhythmic patterns could be evoked in all three thoracic ganglia, but the segmental rhythms differed in their sensitivities to pilocarpine, their frequencies, and the phase relationships of motor neuron antagonists. These different patterns could be generated by a simple adaptable model circuit, which was both simulated and implemented in VLSI hardware. The intersegmental coordination of leg motor rhythms was then examined in preparations of isolated chains of thoracic ganglia. Correlations between motor patterns in different thoracic ganglia indicated that central coupling between segmental pattern generators is likely to contribute to the coordination of the legs during walking. The work described here clearly demonstrates that segmental pattern generators for walking exist in insects. The pattern generators produce motor outputs which are likely to contribute to the coordination of the joints of a limb, as well as the coordination of different limbs. These studies lay the groundwork for further studies to determine the relative contributions of central and sensory neural mechanisms to terrestrial walking.

Plasticity of interneuronal networks of the functionally isolated human spinal cord

There are various neuron models which can be used to emulate the neural networks responsible for cortical and spinal processes. One example is the Central Pattern Generator (CPG) networks, which are spinal neural circuits responsible for controlling the timing of periodic systems in vertebrates. In order to model the CPG effectively, it is necessary to model not just multiple individual neurons, but also the interactions between them. Due to the complexity of these types of systems, CPG models typically require large numbers (> 10) of parameters making them difficult to understand and control. Genetic Algorithms (GAs) provide a means for optimizing systems with many parameters. We present an automated method that uses a GA to And sets of parameters for a silicon implementation of a neural network capable of producing CPG type signals. This methodology can be used to configure large silicon neural circuits. In this work, constructed networks involving an 18-parameter space, can be used for controlling legged robots and neuroprosthetic devices.

This paper examines how electrical stimulation of the spinal cord can modulate the output of the central pattern generator (CPG) for locomotion. Application of discrete current pulses to a single spinal segment was shown to affect multiple parameters of an ongoing locomotor pattern in an in vitro spinal cord. For any given stimulus, the effects on frequency, duration, and symmetry of locomotor output were strongly dependent on the phase at which stimulation was applied within the CPG cycle. Additionally, most stimuli had an immediate impact and evinced no effects on subsequent cycles. The most dramatic changes were seen when stimulation was applied during motor bursting: stimuli applied to the ipsilateral spinal hemicord increased the burst length, while stimuli applied to the contralateral spinal hemicord decreased the burst length. Smaller changes were observed when stimulating during delays between motor bursts. Thus, phasic stimulation was shown to influence the behavior of the CPG and spinal locomotion circuits on a cycle-by-cycle basis. This work represents the first step toward our ultimate goal of developing a neuroprosthetic device to restore locomotion after a severe spinal cord injury.

To generate movements, the motor cortex acts on an intricate network of intermediate neurons in the brainstem and spinal cord, termed ‘premotor neurons’. Premotor neurons activate the motoneurons driving the muscles (Chakrabarti & Schwarz, 2014). Specifically, premotor networks are involved in the generation of reflexes, and form central pattern generators (CPGs) that contribute to stereotyped movement patterns. The precise anatomical organization of these premotor networks is poorly understood, because traditional tract tracing methods lack the specificity to trace tangled networks and are unable to reveal multi-synaptic networks. In this issue of EJN, Sreenivasan et al. (2015) describe evidence that extends previous work by Takatoh et al. (2013), and identify key components of the premotor networks in developing mouse pups. The authors used an elegant neuroanatomical technique called monosynaptic retrograde tracing (MRT) (Wickersham et al., 2007). MRT employs a genetically defective rabies virus that requires a glycoprotein complement in order for the virus to cross a synapse retrogradely and infect the presynaptic neuron. An essential component of this method is the use of genetic engineering to express the required glycoprotein exclusively in postsynaptic neurons, thereby allowing the virus to pass exactly one synapse and exclusively label ‘first-order’ presynaptic neurons. Applied in combination with immunohistochemistry to visualize transmitter content, MRT serves as a powerful tool with which to dissect the anatomical organization of premotor networks. The current study by Sreenivasan et al., and the former study by Takotah et al., investigated the rodent vibrissal system. Whisking movements consist of rhythmic protractions and retractions that are generated by the activation of two antagonistic muscle groups, the intrinsic and extrinsic muscles, respectively. Upon injection of the defective rabies virus into the antagonistic sets of whisker muscles, both studies revealed a fairly consistent anatomical organization of clusters of first-order ‘whisking’ premotor neurons. Among them are known CPGs in the reticular formation, reticular formation cell clusters with unknown function, cells in the spinal trigeminal nuclei, cells in the vestibular nuclei, and, interestingly, also motor cortex neurons. These results contribute greatly to our understanding of this specialized motor system in rodents. Moreover, the current work indicated a fundamental distinction between premotor networks driving extrinsic muscle groups and those driving intrinsic muscle groups. Extrinsic motoneurons are targeted predominantly by excitatory spinal trigeminal and vestibular neurons, whereas intrinsic motoneurons receive relatively more inputs from whisking CPGs. Sreenivasan et al. also combined MRT with anterograde tracing from primary sensorimotor whisker-related cortices [motor, whisker motor cortex (wM1); tactile, primary whisker somatosensory cortex (wS1)] to show that the target profiles of wM1 and wS1 complement the innervation pattern seen for the extrinsic vs. intrinsic premotor systems: wM1 preferentially controls the intrinsic muscle group via the whisking CPG, whereas wS1 controls the extrinsic muscle group via the spinal trigeminal nuclei. Furthermore, the authors could elicit distinct evoked whisker movements after optogenetic activation of the two areas: stimulation in wM1 initiated rhythmic movement, whereas in wS1 it evoked whisker retraction. Although this observation clearly points to differences in motor control between the two cortical areas, it is questionable whether these evoked movements reflect specialization in terms of movement types. First, wM1 is subdivided in several functionally distinct areas, at least in rats (Chakrabarti & Schwarz, 2014). Second, the interpretation of results from bulk activation of motor structures requires caution. Movements evoked from wS1 may merely reflect modulatory action on the whisking brainstem reflex arc (Nguyen & Kleinfeld, 2005), or alternatively its involvement in corticobulbar control of active touch (Furuta et al., 2010). Consistent with these assumptions, we used bulk stimulation to identify the rhythmic whisking subarea of the rat wM1 (Haiss & Schwarz, 2005), and found that it codes for both whisker position and whisking frequency. These effects occurred on the scale of seconds, and therefore possibly reflect indirect control of movement through various premotor networks (Gerdjikov et al., 2013). Rather than attributing distinct types of movement to specific cortical areas, it may be more informative to focus on the differential access of the sensorimotor cortex to specific premotor subsystems, such as CPGs and reflex arcs. In summary, the findings of Sreenivasan et al. (2015), together with the recent discovery of the whisking CPG (Moore et al., 2013), constitute considerable progress towards the description of the whisker-related premotor network. More work will be required to classify the premotor neuron clusters identified so far into functional subsystems. For example, some of the premotor neurons in reticular formation and spinal trigeminal nuclei may well be components of the brainstem reflex arc (Nguyen & Kleinfeld, 2005). Disentangling the entire polysynaptic premotor network will probably require a multifaceted strategy, including additional ingenious genetic trickery, tracing polysynaptic networks in adult animals, and old-fashioned monitoring of the activity of premotor neurons during whisking behavior.

Neurons with axons that extend to the contralateral side of the spinal cord--commissural interneurons (CINs)--coordinate left/right alternation during locomotion. Little is known about the organization of CINs in the mammalian spinal cord. To determine the numbers, distribution, dendritic morphologies, axonal trajectories, and termination patterns of CINs located in the lumbar spinal cord of the neonatal rat, several different retrograde and anterograde axonal tracing paradigms were performed with fluorescent dextran amines and the lipophilic tracer 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). CINs with ascending (aCINs) and descending (dCINs) axons were labeled independently. The aCINs and dCINs occupied different but overlapping domains within the transverse plane. The aCINs were clustered into four recognizable groups, and the dCINs were clustered into two recognizable groups. All dCINs and most aCINs were located within the gray matter, with somata ranging from 10-30 microm in diameter and with large, multipolar dendritic trees. One group of aCINs was located outside the gray matter along the dorsal and dorsolateral margin and had dendrites that were nearly confined to the dorsolateral surface. All CIN axons traversed the ventral commissure at right angles to the midline. CIN axons coursed up to six or seven segments rostrally and/or caudally in the ventral and ventrolateral white matter and gave off collaterals over a shorter range, predominantly to the ventral gray matter. These findings show that the lumbar spinal cord of the neonatal rat contains substantial numbers of CINs with axon projections and collateral ranges spanning several segments and that CINs projecting rostrally vs. caudally have different distributions in the transverse plane. The study provides an anatomical framework for future electrophysiological studies of the spinal neuronal circuits underlying locomotion in mammals.