Central pattern generators in the brainstem and spinal cord: an overview of basic principles, similarities and differences.

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.

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.

To obtain a comprehensive map of the brainstem and spinal cord areas that project to the mesencephalic central gray small injections of horseradish peroxidase were made into various regions of the periaqueductal gray in a series of monkeys. Despite the fact that different regions of the central gray were injected in separate animals, the majority of the brainstem areas containing retrogradely filled neurons remained the same. Labeled neurons were observed in the superior colliculus, periaqueductal gray, lateral parabrachial, locus coeruleus, nucleus raphe magnus and pallidus, and a variety of brainstem reticular nuclei. In contrast to labeled brainstem areas, where labeled neurons were present predominantly ipsilateral to the injection site, the spinal trigeminal nucleus pars caudalis and the spinal cord displayed labeled cells chiefly on the side contralateral to the injection. Also in contrast to the labeled brainstem sites, where medial and lateral injection sites produced a similar pattern of labeling, medial injections in the PAG labeled almost exclusively neurons in the deep laminae (V-X) in the spinal trigeminal nucleus pars caudalis and spinal cord while more lateral injections labeled neurons in both the deep (V-X) and superficial (I) laminae. No consistent differences were noted in the location of labeled neurons in either brainstem or spinal sites after dorsal vs. ventral injections or caudal vs. rostral injection sites. The present study has demonstrated that the central gray receives afferent projections from a number of brainstem and spinal areas which are known to be involved in the modulation and/or conduction of nociception, while other inputs are probably involved in the regulation of visceral functions. These data support the hypothesis that the mesencephalic periaqueductal gray functions as a visceral, nociceptive, and cognitive integrator.

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),

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

To compare morphometric factors of cervical spine in the cervical stenosis on dynamic and static magnetic resonance imaging. To analyse the relationship between the severity of myelopathy and morphometric parameters. Patients with cervical canal stenosis scanned with MRI in neutral (N), flexion (F) and extension (E) positions were retrospectively reviewed. All cases were evaluated in Nurick and Muhle grades. Following parameters were measured: anterior and posterior length of the cervical cord (aLCC, pLCC), mid-cord distance (L value), cervical cord angle (CCA), cervical lordosis, spine/cord (S/C) angle ratio, spinal cord (SC) area, cerebrospinal fluid (CSF) area, and CSF reserve ratio (CSF/CSF plus SC). Univariate multiple regression for Nurick grade as dependent factor was used. Sixty-three patients and 34 men, with the mean age of 58.2 ± 11years, were analysed. Significant differences were found for pLCC, SC area, C lordosis and CCA. The difference between F and E for C lordosis angle was 42.80° ± 14.4 and for CC angle 30.42° ± 9.6. The mean S/C angle ratio was calculated for 1.4 ± 1.3. Nurick grade positively correlated with age (p = 0.041) and S/C angle ratio (p = 0.011), negatively with SC area (p = 0.006) and flexion-extension difference of L value (0.004). Severity of myelopathy correlates with age, spinal cord area on extension and reduced mobility of spinal cord. An association between spine/cervical cord angle mismatch and Nurick grade was found.

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.

Electrical coupling is important in rhythm generating systems. We examine its role in circuits controlling locomotion in a simple vertebrate model, the young Xenopus tadpole, where the hindbrain and spinal cord excitatory descending interneurons (dINs) that drive and maintain swimming have been characterised. Using simultaneous paired recordings, we show that most dINs are electrically coupled exclusively to other dINs (DC coupling coefficients ∼8.5%). The coupling shows typical low-pass filtering. We found no evidence that other swimming central pattern generator (CPG) interneurons are coupled to dINs or to each other. Electrical coupling potentials between dINs appear to contribute to their unusually reliable firing during swimming. To investigate the role of electrical coupling in swimming, we evaluated the specificity of gap junction blockers (18-β-GA, carbenoxolone, flufenamic acid and heptanol) in paired recordings. 18-β-GA at 40–60 μm produced substantial (84%) coupling block but few effects on cellular properties. Swimming episodes in 18-β-GA were significantly shortened (to ∼2% of control durations). At the same time, dIN firing reliability fell from nearly 100% to 62% of swimming cycles and spike synchronization weakened. Because dINs drive CPG neuron firing and are critical in maintaining swimming, the weakening of dIN activity could account for the effects of 18-β-GA on swimming. We conclude that electrical coupling among pre motor reticulospinal and spinal dINs, the excitatory interneurons that drive the swimming CPG in the hatchling Xenopus tadpole, may contribute to the maintenance of swimming as well as synchronization of activity.

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 the central nervous system (CNS), central pattern generators (CPGs) are generally considered as specialized networks that can produce oscillatory motor output in the absence of any oscillatory input. For instance, respiration and mastication are among the critical biological functions well known to be controlled by such specialized networks. Several other CPGs have also been found specifically in the spinal cord. Among them, the CPG for locomotion is probably the most extensively studied rhythm- and pattern-generating network of the CNS. Other, less completely understood CPGs have also been associated with the control of scratching, micturition, and ejaculation. This review provides a brief update on CPG organization and function in the spinal cord and focuses on similarities and differences between these networks and their pharmacological modulation.

Caudal to the forebrain, the generation of basic locomotion is thought to involve a network of neurons in the brainstem and spinal cord. This network consists of the mesencephalic locomotor region (MLR), reticulospinal neurons in the pontomedullary region, and spinal cord locomotor central pattern generators (CPGs).1 In humans, spinal CPGs are thought to be sufficient for generating stepping movement when activated by appropriate sensory or descending inputs.2 However, the anatomic location of descending pathways connecting brainstem and spinal CPGs that initiate stepping movement has not been defined in humans. Here we describe a remarkable patient who developed transient, bilateral, and uncontrollable stepping movements following unintentional puncture injury at the C2 spinal cord level. ### Case report. A 35-year-old woman with unexplained, unremitting headache underwent a diagnostic cervical spinal tap after an unsuccessful lumbar tap. The cervical tap was complicated by cord puncture, immediately after which the patient developed uncontrollable bilateral stepping movements while supine. The stepping movements involved rhythmic, bilateral hip and knee flexion and extension, and occurred paroxysmally about four to five cycles per minute. Simultaneously the patient described an ill-defined urge to move her legs, but stated that this was not in response to pain or discomfort. Neurologic examination identified …

While walking in a straight path, changes in speed result mainly from adjustments in the duration of the stance phase while the swing phase remains relatively invariant, a basic feature of the spinal central pattern generator (CPG). To produce a broad range of locomotor behaviors, the CPG has to integrate modulatory inputs from the brain and the periphery and alter these swing/stance characteristics. In the present work we raise the issue as to whether the CPG can adapt or reorganize in response to a chronic change of supraspinal inputs, as is the case after spinal cord injury (SCI). Kinematic data obtained from six adult cats walking at different treadmill speeds were collected to calculate the cycle and subphase duration at different stages after a first spinal hemisection at T(10) and after a subsequent complete SCI at T(13) respectively aimed at disconnecting unilaterally and then totally the spinal cord from its supraspinal inputs. The results show, first, that the neural control of locomotion is flexible and responsive to a partial or total loss of supraspinal inputs. Second, we demonstrate that a hemisection induces durable plastic changes within the spinal locomotor circuitry below the lesion. In addition, this study gives new insights into the organization of the spinal CPG for locomotion such that phases of the step cycle (swing, stance) can be independently regulated for adapting to speed and also that the CPGs controlling the left and right hindlimbs can, up to a point, be regulated independently.

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.

Locomotion is a complex, rhythmic motor activity involving well-coordinated activation of multiple muscle groups. Locomotor central pattern generators (CPG) are neural circuits located in the thoracolumbar spinal cord which generate the basic rhythm and pattern for locomotion. These circuits integrate descending commands and afferent feedback to produce context-appropriate gait, but the basic motor pattern can be produced independent of both signals. As a result, recruitment of CPGs may have therapeutic relevance for gait improvement following pathologies affecting descending controls, such as stroke or spinal cord injury. Locomotor CPGs have been proposed to have a two-layer structure, in which a rhythm-generating layer produces rhythmic neural bursts and directs a pattern-forming layer to coordinate and recruit appropriate motor modules. Neurons which express the transcription factor Shox2 early in development are involved in both layers and can be divided based on overlap with the V2a interneuron class. Non-V2a Shox2 neurons are implicated in rhythm generation, while V2a Shox2 neurons contribute to motor neuron recruitment. Because rhythm-generating neurons are at the root of CPG function, modulation of non-V2a Shox2 neurons should strongly affect locomotor function. We therefore sought to determine whether and how afferent feedback and interactions with other CPG neurons contributed to the regulation of Shox2 neuron activity. Electrical stimulation of functionally-specified ankle afferents revealed that Shox2 neurons receive highly stereotyped patterns of afferent feedback, consistent with perturbations of ongoing locomotor activity in these preparations. Synaptic inputs to non-V2a Shox2 neurons were modulated rhythmically during locomotion and were reduced following hemisection, suggesting a strong commissural component. Based on this finding, computational modeling of left-right interactions revealed that inhibitory inputs from contralateral CPGs could contribute to maintenance of Shox2 rhythmicity across a wide range of descending drive strengths and produce moderate increases in maximum locomotor frequency. Together, these results provide cellular mechanisms acting presynaptically on rhythm-generating neurons that enable context-appropriate adjustments to locomotor function. Keywords: central pattern generator, locomotion, rhythm generation, sensory afferents, shox2, spinal interneuron

Spinal cord pattern generators for locomotion.