Spinal Locomotor Research Articles

Nigral Glutamatergic Neurons Control the Speed of Locomotion.

The mesencephalic locomotor region (MLR) plays a crucial role in locomotor control. In vertebrates, stimulation of the MLR at increasing intensities elicits locomotion of growing speed. This effect has been presumed to result from higher brain inputs activating the MLR like a dimmer switch. Here, we show in lampreys (Petromyzon marinus) of either sex that incremental stimulation of a region homologous to the mammalian substantia nigra pars compacta (SNc) evokes increasing activation of MLR cells with a graded increase in the frequency of locomotor movements. Neurons co-storing glutamate and dopamine were found to project from the primal SNc to the MLR. Blockade of glutamatergic transmission largely diminished MLR cell responses and locomotion. Local blockade of D1 receptors in the MLR decreased locomotor frequency, but did not disrupt the SNc-evoked graded control of locomotion. Our findings revealed the presence of a glutamatergic input to the MLR originating from the primal SNc that evokes graded locomotor movements.SIGNIFICANCE STATEMENT The mesencephalic locomotor region (MLR) plays a crucial role in the control of locomotion. It projects downward to reticulospinal neurons that in turn activate the spinal locomotor networks. Increasing the intensity of MLR stimulation produces a growing activation of reticulospinal cells and a progressive increase in the speed of locomotor movements. Since the discovery of the MLR some 50 years ago, it has been presumed that higher brain regions activate the MLR in a graded fashion, but this has not been confirmed yet. Here, using a combination of techniques from cell to behavior, we provide evidence of a new glutamatergic pathway activating the MLR in a graded fashion, and consequently evoking a progressive increase in locomotor output.

Lack of adaptation during prolonged split-belt locomotion in the intact and spinal cat.

During split-belt locomotion in humans where one leg steps faster than the other, the symmetry of step lengths and double support periods of the slow and fast legs is gradually restored. When returning to tied-belt locomotion, there is an after-effect, with a reversal in the asymmetry observed in the early split-belt period, indicating that the new pattern was stored within the central nervous system. In this study, we investigated if intact and spinal-transected cats show a similar pattern of adaptation to split-belt locomotion by measuring kinematic variables and electromyography before, during and after 10min of split-belt locomotion. The results show that cats do not adapt to prolonged split-belt locomotion. Our results suggest an important physiological difference in how cats and humans respond to prolonged asymmetric locomotion. In humans, gait adapts to prolonged walking on a split-belt treadmill, where one leg steps faster than the other, by gradually restoring the symmetry of interlimb kinematic variables, such as double support periods and step lengths, and by reducing muscle activity (EMG, electromyography). The adaptation is also characterized by reversing the asymmetry of interlimb variables observed during the early split-belt period when returning to tied-belt locomotion, termed an after-effect. To determine if cats adapt to prolonged split-belt locomotion and to assess if spinal locomotor circuits participate in the adaptation, we measured interlimb variables and EMG in intact and spinal-transected cats before, during and after 10min of split-belt locomotion. In spinal cats, only the hindlimbs performed stepping with the forelimbs stationary. In intact and spinal cats, step lengths and double support periods were, on average, symmetric, during tied-belt locomotion. They became asymmetric during split-belt locomotion and remained asymmetric throughout the split-belt period. Upon returning to tied-belt locomotion, symmetry was immediately restored. In intact cats, the mean EMG amplitude of hindlimb extensors increased during split-belt locomotion and remained increased throughout the split-belt period, whereas in spinal cats, EMG amplitude did not change. Therefore, the results indicate that the locomotor pattern of cats does not adapt to prolonged split-belt locomotion, suggesting an important physiological difference in the control of locomotion between cats and humans. We propose that restoring left-right symmetry is not required to maintain balance during prolonged asymmetric locomotion in the cat, a quadruped, as opposed to human bipedal locomotion.

Sodium pump regulation of locomotor control circuits.

Sodium pumps are ubiquitously expressed membrane proteins that extrude three Na+ ions in exchange for two K+ ions, using ATP as an energy source. Recent studies have illuminated additional, dynamic roles for sodium pumps in regulating the excitability of neuronal networks in an activity-dependent fashion. We review their role in a novel form of short-term memory within rhythmic locomotor networks. The data we review derives mainly from recent studies on Xenopus tadpoles and neonatal mice. The role and underlying mechanisms of pump action broadly match previously published data from an invertebrate, the Drosophila larva. We therefore propose a highly conserved mechanism by which sodium pump activity increases following a bout of locomotion. This results in an ultraslow afterhyperpolarization (usAHP) of the membrane potential that lasts around 1 min, but which only occurs in around half the network neurons. This usAHP in turn alters network excitability so that network output is reduced in a locomotor interval-dependent manner. The pumps therefore confer on spinal locomotor networks a temporary memory trace of recent network performance.

Probing the Human Spinal Locomotor Circuits by Phasic Step-Induced Feedback and by Tonic Electrical and Pharmacological Neuromodulation.

The mammalian lumbar spinal cord experimentally isolated from supraspinal and afferent feedback input remains capable of expressing some basic locomotor function when appropriately stimulated. This ability has been attributed to spinal neural circuits referred to as central pattern generators (CPGs). In individuals with a severe spinal cord injury, rhythmic activity in paralyzed leg muscles can be generated by phasic proprioceptive feedback during therapist- or robotic-assisted stepping on a motorized treadmill. Here, we critically review to what extent the resulting motor output represents locomotor-like activity, and whether these motor patterns are the result of activation of CPGs, as commonly suggested in the literature. Attempts will be made to further delineate the pivotal roles played by mechanisms such as spinal proprioceptive reflexes and their alterations after spinal cord injury, the central excitability level, and by neurotransmitters critical for spinal locomotor activity. We will discuss the view that the muscle activity produced during assisted passive treadmill stepping is resulting from the entrainment of spinal reflex circuits by the cyclically generated proprioceptive feedback. We suggest that the activation of CPG circuits depends rather on the presence of a sustained tonic excitatory drive, as can be provided by electrical spinal cord stimulation, or by specific combinations of dopaminergic agonists, adrenergic/ dopaminergic precursors and/or 5-HT receptor agonists. Novel rehabilitation strategies using spinal cord stimulation and rhythmic-activity producing drugs during locomotor therapy will pave the way for clinically relevant advances in restoration of motor function in people with severe spinal cord injury.

Double-Blind, Placebo-Controlled, Randomized Phase I/IIa Study (Safety and Efficacy) with Buspirone/Levodopa/Carbidopa (SpinalonTM) in Subjects with Complete AIS A or Motor-Complete AIS B Spinal Cord Injury.

No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking. Single administration of buspirone/levodopa/carbidopa (SpinalonTM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM-treated groups displayed significant EMG activity accompanied by locomotor-like characteristics - that is with rhythmic and bilaterally alternating bursts. Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI.

Tonic and Rhythmic Spinal Activity Underlying Locomotion.

In recent years, many researches put significant efforts into understanding and assessing the functional state of the spinal locomotor circuits in humans. Various techniques have been developed to stimulate the spinal cord circuitries, which may include both diffuse and quite specific tuning effects. Overall, the findings indicate that tonic and rhythmic spinal activity control are not separate phenomena but are closely integrated to properly initiate and sustain stepping. The spinal cord does not simply transmit information to and from the brain. Its physiologic state determines reflex, postural and locomotor control and, therefore, may affect the recovery of the locomotor function in individuals with spinal cord and brain injuries. This review summarizes studies that examine the rhythmogenesis capacity of cervical and lumbosacral neuronal circuitries in humans and its importance in developing central pattern generator-modulating therapies.

Rationale for Assessing Safety and Efficacy of Drug Candidates Alone and in Combination with Medical Devices: The Case Study of SpinalonTM.

The aim of this review is to describe the rationale and main underlying reasons for undertaking, during clinical development, the study of drug candidates used separately and/or in combination with other technologies. To ease comprehension, reference will be made to the case of SpinalonTM, a new fixed-dose combination (FDC) product composed of levodopa/carbidopa/buspirone. This drug is capable of triggering, within minutes after a single administration orally, 45 minute- episodes of basic involuntary 'reflex' walking in paraplegic animals. Daily administration during one month was shown to lead to increased performance over time, with health benefits onto musculoskeletal and cardiovascular systems. A double-blind, dose-escalation, randomized phase I/IIa study with 45 spinal cord-injured subjects successfully provided the maximal tolerated dose (MTD) and preliminary evidence of efficacy. As an attempt to explore how efficacy may be optimized, a phase IIb study with 150 subjects was designed to compare the effects of repeated administration in different conditions (arms). Tests with a motorized treadmill, a harness for body weight support, a transdermal spinal cord stimulator and/or an exoskeleton were proposed because: 1) these devices are unlikely to alter safety but, 2) they are reasonably expected to increase spinal locomotor neuron activation, reflex walking induction, and musculoskeletal/cardiovascular benefits. This approach would normally allow the phase III study to demonstrate clearly, with fewer subjects and at lower costs, long-term benefits on health of SpinalonTM used in optimized conditions and settings. This innovative strategy in drug development may contribute to further describe the mechanisms of action as well as optimized conditions of use for patients. Adapted to the development of other products, such an approach may enable greater safety, efficacy, clinical utility and compliance to be sought for next-generation CNS drugs.

Neuromodulation of Spinal Locomotor Networks in Rodents.

The basic motor patterns driving rhythmic limb movements during walking are generated by networks of neurons called central pattern generators (CPGs). Within motor control systems, neuromodulators are necessary for proper and efficient CPG function because they induce or regulate essential components of spinal network activity, including firing parameters of CPG neurons and network synaptic strength, allowing the network to change/adapt and sometimes to even become functional. The goal of this work is to focus on classical and recent findings addressing the role of neuromodulators such as glutamate, dopamine, acetylcholine and adenosine in eliciting, changing and sometimes terminating spinal CPG network function in rodents. Neuromodulatory inputs onto CPG locomotor networks have been additionally related to inducing state changes such as locomotor timing, phasing and speed, and to the induction/maintenance of actual network function. These inputs originate from supraspinal centers such as the brainstem and from intraspinal neurotransmission. The isolated in vitro rodent spinal cord preparation is a powerful model for studies on locomotor network organization because of its physiological and anatomical accessibility, as well as the incorporation of various transgenic approaches to identify specific neuronal populations. Both roles are accomplished through the action of neuromodulators on ionotropic and metabotropic receptors mediating synaptic neurotransmission, which can be used by neurons that are intrinsic or extrinsic components of a CPG network itself. This article has hopefully provided a comprehensive overview of some of the main spinal mechanisms involved in the modulatory control of locomotor activity.

Ladder Treadmill: A Method to Assess Locomotion in Cats with an Intact or Lesioned Spinal Cord.

After lesions of the CNS, locomotor abilities of animals (mainly cats) are often assessed on a simple flat treadmill (FTM), which imposes little demands on supraspinal structures as is the case when walking on targets. Therefore, the aims of the present work were as follows: (1) to develop a treadmill allowing the assessment of locomotion of intact cats required to place the paws on the rungs of a moving ladder treadmill (LTM); (2) to assess the capability of cats after a unilateral spinal hemisection at T10 to cope with such a demanding locomotor task; and (3) to regularly train cats for 6 weeks on the LTM to determine whether such regular training improves locomotor recovery on the FTM. A significant improvement would indicate that LTM training maximizes the contribution of spinal locomotor circuits as well as remnant supraspinal inputs. Together, we used 9 cats (7 females, 2 males). Six were used to compare the EMG and kinematic locomotor characteristics during walking on the FTM and LTM. We found that the swing phase during LTM walking was slightly enhanced as well as some specific activity of knee flexor muscles. Fore-hindlimb coupling favored a more stable diagonal coupling. These 6 cats were then hemispinalized and trained for 6 weeks on the LTM, whereas the 3 other cats were hemispinalized and trained solely on the FTM to compare the two training regimens. Intensive LTM training after hemisection was found to change features of locomotion, such as the foot trajectory as well as diminished paw drag often observed after hemisection.SIGNIFICANCE STATEMENT This paper introduces a method (ladder treadmill [LTM]) to study the locomotor ability of cats with an intact spinal cord or after a unilateral hemisection to walk with a precise foot placement on the rungs fixed to an ordinary flat treadmill (FTM). Because cats are compared in various conditions (intact or hemisected at different time points) in the same enclosure on the FTM and the LTM, the changes in averaged locomotor characteristics must reflect the specificity of the task and the neurological states. Furthermore, the ladder treadmill permits to train cats repetitively for weeks and observe whether training regimens (FTM or LTM) can induce durable changes in the parameters of locomotion.

Serotonergic projections to lumbar levels and its plasticity following spinal cord injury

The descending serotonergic pathway, which originates in various populations of brainstem neurons, plays an important role in generating the rhythmic motor pattern associated with locomotor movement. Although the development of its innervation has been studied in rodent spinal cord, it has not been clearly identified how the projection of serotonergic pathway is related to its function. Here, we evaluated the pattern of serotonergic innervation on the lumbar spinal cord from embryonic day 14.5 (E14.5) to adulthood. Before birth, we found that 5-hydroxytryptamine (5-HT) fibers invade the lumbar cord as early as E14.5, penetrate into the gray matter from lateral funiculus by E16.5, and then mainly occupied the ventral horn by E18.5 before localizing in the dorsal horn. After birth, we found that 5-HT invasion of both dorsal horn and ventral horn were present by the 7th postnatal day (P7). Additionally, the 5-HT innervation of these two areas evolved progressively from a diffuse network to a more restricted pattern, particularly at the ventral horn within the motoneuron area from P21 to adulthood. This 5-HT innervation pattern in the lumbar cord provides anatomical evidence that serotonergic fibers establish direct connections with lumbar motoneurons, which offers us a solid foundation that enhancing the plasticity of serotonergic pathway following SCI may facilitate locomotor functional recovery. Therefore, we employed treadmill training to activate serotonergic plasticity after SCI. We found that mice which underwent treadmill training exhibited a better locomotor functional recovery. Meanwhile, the density of 5-HT fibers in the ventral horn was significantly increased and the synaptic formation of 5-HT fibers with lumbar motoneurons was also significantly rescued in the training group mice after SCI. These findings demonstrate that the descending serotonergic projection is a robust and flexible parallel pathway for modulating spinal locomotor function.

Acquisition of Involuntary Spinal Locomotion (Spinal Walking) in Dogs with Irreversible Thoracolumbar Spinal Cord Lesion: 81 Dogs.

BackgroundSpinal walking (SW) is described as the acquisition of an involuntary motor function in paraplegic dogs and cats without pain perception affected by a thoracolumbar lesion. Whereas spinal locomotion is well described in cats that underwent training trials after experimental spinal cord resection, less consistent information is available for dogs.HypothesisParaplegic dogs affected by a thoracolumbar complete spinal cord lesion undergoing intensive physical rehabilitation could acquire an autonomous SW gait under field conditions.AnimalsEighty‐one acute paraplegic thoracolumbar dogs without pelvic limb pain perception.MethodsRetrospective study of medical records of dogs selected for intensive rehabilitation treatment in paraplegic dogs with absence of pain perception on admission and during the whole treatment. Binary regression and multivariate logistic regression were used to analyze potential associations with the development of SW.ResultsAutonomous SW was achieved in 48 dogs (59%). Median time to achieve SW was of 75.5 days (range: 16–350 days). On univariate analysis, SW gait was associated with younger age (P = .002) and early start of physiotherapy (P = .024). Multivariate logistic regression showed that younger age (≤60 months) and lightweight (≤7.8 kg) were positively associated with development of SW (P = .012 and P < .001, respectively). BCS, full‐time hospitalization, and type and site of the lesion were not significantly associated with development of SW.ConclusionsDogs with irreversible thoracolumbar lesion undergoing intensive physiotherapic treatment can acquire SW. Younger age and lightweight are positively associated with the development of SW gait.

Differential regulation of NMDA receptors by d-serine and glycine in mammalian spinal locomotor networks.

Activation of N-methyl-d-aspartate receptors (NMDARs) requires the binding of a coagonist, either d-serine or glycine, in addition to glutamate. Changes in occupancy of the coagonist binding site are proposed to modulate neural networks including those controlling swimming in frog tadpoles. Here, we characterize regulation of the NMDAR coagonist binding site in mammalian spinal locomotor networks. Blockade of NMDARs by d(-)-2-amino-5-phosphonopentanoic acid (d-APV) or 5,7-dichlorokynurenic acid reduced the frequency and amplitude of pharmacologically induced locomotor-related activity recorded from the ventral roots of spinal-cord preparations from neonatal mice. Furthermore, d-APV abolished synchronous activity induced by blockade of inhibitory transmission. These results demonstrate an important role for NMDARs in murine locomotor networks. Bath-applied d-serine enhanced the frequency of locomotor-related but not disinhibited bursting, indicating that coagonist binding sites are saturated during the latter but not the former mode of activity. Depletion of endogenous d-serine by d-amino acid oxidase or the serine-racemase inhibitor erythro-β-hydroxy-l-aspartic acid (HOAsp) increased the frequency of locomotor-related activity, whereas application of l-serine to enhance endogenous d-serine synthesis reduced burst frequency, suggesting a requirement for d-serine at a subset of synapses onto inhibitory interneurons. Consistent with this, HOAsp was ineffective during disinhibited activity. Bath-applied glycine (1-100 µM) failed to alter locomotor-related activity, whereas ALX 5407, a selective inhibitor of glycine transporter-1 (GlyT1), enhanced burst frequency, supporting a role for GlyT1 in NMDAR regulation. Together these findings indicate activity-dependent and synapse-specific regulation of the coagonist binding site within spinal locomotor networks, illustrating the importance of NMDAR regulation in shaping motor output.NEW & NOTEWORTHY We provide evidence that NMDARs within murine spinal locomotor networks determine the frequency and amplitude of ongoing locomotor-related activity in vitro and that NMDARs are regulated by d-serine and glycine in a synapse-specific and activity-dependent manner. In addition, glycine transporter-1 is shown to be an important regulator of NMDARs during locomotor-related activity. These results show how excitatory transmission can be tuned to diversify the output repertoire of spinal locomotor networks in mammals.

Developmental role of DSCAM in spinal locomotor circuits.

Studying the development of spinal circuitry is essential in understanding the motor behaviors that arise from them. In their study, Thiry et al. (J Neurophysiol 115: 1338-1354, 2016) show that loss of Down syndrome cell adhesion molecule (DSCAM) leads to locomotor impairments that may stem from specific changes in spinal connectivity altering the balance of central and peripheral excitatory drive onto spinal motoneurons. These findings as well as additional insights and future directions are discussed in the context of the recent literature.

Spinal Hb9::Cre-derived excitatory interneurons contribute to rhythm generation in the mouse

Rhythm generating neurons are thought to be ipsilaterally-projecting excitatory neurons in the thoracolumbar mammalian spinal cord. Recently, a subset of Shox2 interneurons (Shox2 non-V2a INs) was found to fulfill these criteria and make up a fraction of the rhythm-generating population. Here we use Hb9::Cre mice to genetically manipulate Hb9::Cre-derived excitatory interneurons (INs) in order to determine the role of these INs in rhythm generation. We demonstrate that this line captures a consistent population of spinal INs which is mixed with respect to neurotransmitter phenotype and progenitor domain, but does not overlap with the Shox2 non-V2a population. We also show that Hb9::Cre-derived INs include the comparatively small medial population of INs which continues to express Hb9 postnatally. When excitatory neurotransmission is selectively blocked by deleting Vglut2 from Hb9::Cre-derived INs, there is no difference in left-right and/or flexor-extensor phasing between these cords and controls, suggesting that excitatory Hb9::Cre-derived INs do not affect pattern generation. In contrast, the frequencies of locomotor activity are significantly lower in cords from Hb9::Cre-Vglut2Δ/Δ mice than in cords from controls. Collectively, our findings indicate that excitatory Hb9::Cre-derived INs constitute a distinct population of neurons that participates in the rhythm generating kernel for spinal locomotion.

Functional Neuroanatomy for Posture and Gait Control.

Here we argue functional neuroanatomy for posture-gait control. Multi-sensory information such as somatosensory, visual and vestibular sensation act on various areas of the brain so that adaptable posture-gait control can be achieved. Automatic process of gait, which is steady-state stepping movements associating with postural reflexes including headeye coordination accompanied by appropriate alignment of body segments and optimal level of postural muscle tone, is mediated by the descending pathways from the brainstem to the spinal cord. Particularly, reticulospinal pathways arising from the lateral part of the mesopontine tegmentum and spinal locomotor network contribute to this process. On the other hand, walking in unfamiliar circumstance requires cognitive process of postural control, which depends on knowledges of self-body, such as body schema and body motion in space. The cognitive information is produced at the temporoparietal association cortex, and is fundamental to sustention of vertical posture and construction of motor programs. The programs in the motor cortical areas run to execute anticipatory postural adjustment that is optimal for achievement of goal-directed movements. The basal ganglia and cerebellum may affect both the automatic and cognitive processes of posturegait control through reciprocal connections with the brainstem and cerebral cortex, respectively. Consequently, impairments in cognitive function by damages in the cerebral cortex, basal ganglia and cerebellum may disturb posture-gait control, resulting in falling.

Effects of spinal cord stimulation on motor functions in children with cerebral palsy

Is it possible to regulate the functional properties of abnormally developed spinal neuronal locomotor networks using transcutaneous spinal cord stimulation? This question has been studied in twenty-eight participants (∼9 yrs) with spastic cerebral palsy, and mainly Gross Motor Function Classification System for Cerebral Palsy level III. The participants were randomly assigned to two groups. The experimental group received transcutaneous spinal cord stimulation at two spinal levels (over T11 and L1 spinous processes), combined with locomotor treadmill training, whereas the participants of the control group received locomotor treadmill training only. After spinal cord stimulation in the experimental group we found an incremental increase in knee torque whereas in the control group this effect was absent. The amplitude of hip motion increased in both groups. A decrease of co-activation of hip and muscles of the lower extremities was observed in the experimental group while in the control group co-activation decreased only in hip muscles. The results support the idea that locomotor function can be improved significantly with the combination of training and transcutaneous spinal cord stimulation than with training alone.

Distinct sets of locomotor modules control the speed and modes of human locomotion.

Although recent vertebrate studies have revealed that different spinal networks are recruited in locomotor mode- and speed-dependent manners, it is unknown whether humans share similar neural mechanisms. Here, we tested whether speed- and mode-dependence in the recruitment of human locomotor networks exists or not by statistically extracting locomotor networks. From electromyographic activity during walking and running over a wide speed range, locomotor modules generating basic patterns of muscle activities were extracted using non-negative matrix factorization. The results showed that the number of modules changed depending on the modes and speeds. Different combinations of modules were extracted during walking and running, and at different speeds even during the same locomotor mode. These results strongly suggest that, in humans, different spinal locomotor networks are recruited while walking and running, and even in the same locomotor mode different networks are probably recruited at different speeds.

Mechanisms of spinal cord electrical stimulation action on autonomic functions

The method of transcutaneous electrical stimulation of the spinal cord (ESSC) has recently begun to be actively used for both experimental studies of human motor functions and the rehabilitation of motor function in patients with spinal cord pathology. The spinal cord is the most important center of the regulation of vital functions, and ESSC affects as spinal locomotor networks as the visceral system too, which should be taken into account for the development of an improved method of rehabilitation and its use in experiments on healthy volunteers. We present a review of studies on the possible mechanisms of ESSC effects on the peripheral and cerebral circulation, cardiovascular, respiratory, excretory, and digestive systems of mammals.

Immature Spinal Locomotor Output in Children with Cerebral Palsy.

Detailed descriptions of gait impairments have been reported in cerebral palsy (CP), but it is still unclear how maturation of the spinal motoneuron output is affected. Spatiotemporal alpha-motoneuron activation during walking can be assessed by mapping the electromyographic activity profiles from several, simultaneously recorded muscles onto the anatomical rostrocaudal location of the motoneuron pools in the spinal cord, and by means of factor analysis of the muscle activity profiles. Here, we analyzed gait kinematics and EMG activity of 11 pairs of bilateral muscles with lumbosacral innervation in 35 children with CP (19 diplegic, 16 hemiplegic, 2–12 years) and 33 typically developing (TD) children (1–12 years). TD children showed a progressive reduction of EMG burst durations and a gradual reorganization of the spatiotemporal motoneuron output with increasing age. By contrast, children with CP showed very limited age-related changes of EMG durations and motoneuron output, as well as of limb intersegmental coordination and foot trajectory control (on both sides for diplegic children and the affected side for hemiplegic children). Factorization of the EMG signals revealed a comparable structure of the motor output in children with CP and TD children, but significantly wider temporal activation patterns in children with CP, resembling the patterns of much younger TD infants. A similar picture emerged when considering the spatiotemporal maps of alpha-motoneuron activation. Overall, the results are consistent with the idea that early injuries to developing motor regions of the brain substantially affect the maturation of the spinal locomotor output and consequently the future locomotor behavior.

Mechanisms underlying the endogenous dopaminergic inhibition of spinal locomotor circuit function in Xenopus tadpoles.

Dopamine plays important roles in the development and modulation of motor control circuits. Here we show that dopamine exerts potent effects on the central pattern generator circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine (0.5–100 μM) reduced fictive swim bout occurrence and caused both spontaneous and evoked episodes to become shorter, slower and weaker. The D2-like receptor agonist quinpirole mimicked this repertoire of inhibitory effects on swimming, whilst the D4 receptor antagonist, L745,870, had the opposite effects. The dopamine reuptake inhibitor bupropion potently inhibited fictive swimming, demonstrating that dopamine constitutes an endogenous modulatory system. Both dopamine and quinpirole also inhibited swimming in spinalised preparations, suggesting spinally located dopamine receptors. Dopamine and quinpirole hyperpolarised identified rhythmically active spinal neurons, increased rheobase and reduced spike probability both during swimming and in response to current injection. The hyperpolarisation was TTX-resistant and was accompanied by decreased input resistance, suggesting that dopamine opens a K+ channel. The K+ channel blocker barium chloride (but not TEA, glybenclamide or tertiapin-Q) significantly occluded the hyperpolarisation. Overall, we show that endogenously released dopamine acts upon spinally located D2-like receptors, leading to a rapid inhibitory modulation of swimming via the opening of a K+ channel.