Computational Modeling of Spinal Locomotor Circuitry in the Age of Molecular Genetics.

Neuronal circuits in the spinal cord are essential for the control of locomotion. They integrate supraspinal commands and afferent feedback signals to produce coordinated rhythmic muscle activations necessary for stable locomotion. For several decades, computational modeling has complemented experimental studies by providing a mechanistic rationale for experimental observations and by deriving experimentally testable predictions. This symbiotic relationship between experimental and computational approaches has resulted in numerous fundamental insights. With recent advances in molecular and genetic methods, it has become possible to manipulate specific constituent elements of the spinal circuitry and relate them to locomotor behavior. This has led to computational modeling studies investigating mechanisms at the level of genetically defined neuronal populations and their interactions. We review literature on the spinal locomotor circuitry from a computational perspective. By reviewing examples leading up to and in the age of molecular genetics, we demonstrate the importance of computational modeling and its interactions with experiments. Moving forward, neuromechanical models with neuronal circuitry modeled at the level of genetically defined neuronal populations will be required to further unravel the mechanisms by which neuronal interactions lead to locomotor behavior.

Intralimb and Interlimb Cutaneous Reflexes during Locomotion in the Intact Cat.

When the foot contacts an obstacle during locomotion, cutaneous inputs activate spinal circuits to ensure dynamic balance and forward progression. In quadrupeds, this requires coordinated reflex responses between the four limbs. Here, we investigated the patterns and phasic modulation of cutaneous reflexes in forelimb and hindlimb muscles evoked by inputs from all four limbs. Five female cats were implanted to record muscle activity and to stimulate the superficial peroneal and superficial radial nerves during locomotion. Stimulating these nerves evoked short-, mid-, and longer-latency excitatory and/or inhibitory responses in all four limbs that were phase-dependent. The largest responses were generally observed during the peak activity of the muscle. Cutaneous reflexes during mid-swing were consistent with flexion of the homonymous limb and accompanied by modification of the stance phases of the other three limbs, by coactivating flexors and extensors and/or by delaying push-off. Cutaneous reflexes during mid-stance were consistent with stabilizing the homonymous limb by delaying and then facilitating its push-off and modifying the support phases of the homolateral and diagonal limbs, characterized by coactivating flexors and extensors, reinforcing extensor activity and/or delaying push-off. The shortest latencies of homolateral and diagonal responses were consistent with fast-conducting disynaptic or trisynaptic pathways. Descending homolateral and diagonal pathways from the forelimbs to the hindlimbs had a higher probability of eliciting responses compared with ascending pathways from the hindlimbs to the forelimbs. Thus, in quadrupeds, intralimb and interlimb reflexes activated by cutaneous inputs ensure dynamic coordination of the four limbs, producing a whole-body response.SIGNIFICANCE STATEMENT The skin contains receptors that, when activated, send inputs to spinal circuits, signaling a perturbation. Rapid responses, or reflexes, in muscles of the contacted limb and opposite homologous limb help maintain balance and forward progression. Here, we investigated reflexes during quadrupedal locomotion in the cat by electrically stimulating cutaneous nerves in each of the four limbs. Functionally, responses appear to modify the trajectory or stabilize the movement of the stimulated limb while modifying the support phase of the other limbs. Reflexes between limbs are mediated by fast-conducting pathways that involve excitatory and inhibitory circuits controlling each limb. The comparatively stronger descending pathways from cervical to lumbar circuits controlling the forelimbs and hindlimbs, respectively, could serve a protective function.

Central control of interlimb coordination and speed-dependent gait expression in quadrupeds.

KEY POINTS: Quadrupeds express different gaits depending on speed of locomotion. Central pattern generators (one per limb) within the spinal cord generate locomotor oscillations and control limb movements. Neural interactions between these generators define interlimb coordination and gait. We present a computational model of spinal circuits representing four rhythm generators with left-right excitatory and inhibitory commissural and fore-hind inhibitory interactions within the cord. Increasing brainstem drive to all rhythm generators and excitatory commissural interneurons induces an increasing frequency of locomotor oscillations accompanied by speed-dependent gait changes from walk to trot and to gallop and bound. The model closely reproduces and suggests explanations for multiple experimental data, including speed-dependent gait transitions in intact mice and changes in gait expression in mutants lacking certain types of commissural interneurons. The model suggests the possible circuit organization in the spinal cord and proposes predictions that can be tested experimentally. ABSTRACT: As speed of locomotion is increasing, most quadrupeds, including mice, demonstrate sequential gait transitions from walk to trot and to gallop and bound. The neural mechanisms underlying these transitions are poorly understood. We propose that the speed-dependent expression of different gaits results from speed-dependent changes in the interactions between spinal circuits controlling different limbs and interlimb coordination. As a result, the expression of each gait depends on (1) left-right interactions within the spinal cord mediated by different commissural interneurons (CINs), (2) fore-hind interactions on each side of the spinal cord and (3) brainstem drives to rhythm-generating circuits and CIN pathways. We developed a computational model of spinal circuits consisting of four rhythm generators (RGs) with bilateral left-right interactions mediated by V0 CINs (V0D and V0V sub-types) providing left-right alternation, and conditional V3 CINs promoting left-right synchronization. Fore and hind RGs mutually inhibited each other. We demonstrate that linearly increasing excitatory drives to the RGs and V3 CINs can produce a progressive increase in the locomotor speed accompanied by sequential changes of gaits from walk to trot and to gallop and bound. The model closely reproduces and suggests explanations for the speed-dependent gait expression observed in vivo in intact mice and in mutants lacking V0V or all V0 CINs. Specifically, trot is not expressed after removal of V0V CINs, and only bound is expressed after removal of all V0 CINs. The model provides important insights into the organization of spinal circuits and neural control of locomotion.

Human spinal locomotor control is based on flexibly organized burst generators.

Constant drive provided to the human lumbar spinal cord by epidural electrical stimulation can cause local neural circuits to generate rhythmic motor outputs to lower limb muscles in people paralysed by spinal cord injury. Epidural spinal cord stimulation thus allows the study of spinal rhythm and pattern generating circuits without their configuration by volitional motor tasks or task-specific peripheral feedback. To reveal spinal locomotor control principles, we studied the repertoire of rhythmic patterns that can be generated by the functionally isolated human lumbar spinal cord, detected as electromyographic activity from the legs, and investigated basic temporal components shared across these patterns. Ten subjects with chronic, motor-complete spinal cord injury were studied. Surface electromyographic responses to lumbar spinal cord stimulation were collected from quadriceps, hamstrings, tibialis anterior, and triceps surae in the supine position. From these data, 10-s segments of rhythmic activity present in the four muscle groups of one limb were extracted. Such samples were found in seven subjects. Physiologically adequate cycle durations and relative extension- and flexion-phase durations similar to those needed for locomotion were generated. The multi-muscle activation patterns exhibited a variety of coactivation, mixed-synergy and locomotor-like configurations. Statistical decomposition of the electromyographic data across subjects, muscles and samples of rhythmic patterns identified three common temporal components, i.e. basic or shared activation patterns. Two of these basic patterns controlled muscles to contract either synchronously or alternatingly during extension- and flexion-like phases. The third basic pattern contributed to the observed muscle activities independently from these extensor- and flexor-related basic patterns. Each bifunctional muscle group was able to express both extensor- and flexor-patterns, with variable ratios across the samples of rhythmic patterns. The basic activation patterns can be interpreted as central drives implemented by spinal burst generators that impose specific spatiotemporally organized activation on the lumbosacral motor neuron pools. Our data thus imply that the human lumbar spinal cord circuits can form burst-generating elements that flexibly combine to obtain a wide range of locomotor outputs from a constant, repetitive input. It may be possible to use this flexibility to incorporate specific adaptations to gait and stance to improve locomotor control, even after severe central nervous system damage.

Periodic modulation of repetitively elicited monosynaptic reflexes of the human lumbosacral spinal cord.

In individuals with motor-complete spinal cord injury, epidural stimulation of the lumbosacral spinal cord at 2 Hz evokes unmodulated reflexes in the lower limbs, while stimulation at 22-60 Hz can generate rhythmic burstlike activity. Here we elaborated on an output pattern emerging at transitional stimulation frequencies with consecutively elicited reflexes alternating between large and small. We analyzed responses concomitantly elicited in thigh and leg muscle groups bilaterally by epidural stimulation in eight motor-complete spinal cord-injured individuals. Periodic amplitude modulation of at least 20 successive responses occurred in 31.4% of all available data sets with stimulation frequency set at 5-26 Hz, with highest prevalence at 16 Hz. It could be evoked in a single muscle group only but was more strongly expressed and consistent when occurring in pairs of antagonists or in the same muscle group bilaterally. Latencies and waveforms of the modulated reflexes corresponded to those of the unmodulated, monosynaptic responses to 2-Hz stimulation. We suggest that the cyclical changes of reflex excitability resulted from the interaction of facilitatory and inhibitory mechanisms emerging after specific delays and with distinct durations, including postactivation depression, recurrent inhibition and facilitation, as well as reafferent feedback activation. The emergence of large responses within the patterns at a rate of 5.5/s or 8/s may further suggest the entrainment of spinal mechanisms as involved in clonus. The study demonstrates that the human lumbosacral spinal cord can organize a simple form of rhythmicity through the repetitive activation of spinal reflex circuits.

Neurocontrol of Movement in Humans With Spinal Cord Injury.

In this review of neurocontrol of movement after spinal cord injury, we discuss neurophysiological evidences of conducting and processing mechanisms of the spinal cord. We illustrate that external afferent inputs to the spinal cord below the level of the lesion can modify, initiate, and maintain execution of movement in absence or partial presence of brain motor control after chronic spinal cord injury. We review significant differences between spinal reflex activity elicited by single and repetitive stimulation. The spinal cord can respond with sensitization, habituation, and dis-habituation to regular repetitive stimulation. Therefore, repetitive spinal cord reflex activity can contribute to the functional configuration of the spinal network. Moreover, testing spinal reflex activity in individuals with motor complete spinal cord injury provided evidences for subclinical residual brain influence, suggesting the existence of axons traversing the injury site and influencing the activities below the level of lesion. Thus, there are two motor control models of chronic spinal cord injury in humans: "discomplete" and "reduced and altered volitional motor control." We outline accomplishments in modification and initiation of altered neurocontrol in chronic spinal cord injury people with epidural and functional electrical stimulation. By nonpatterned electrical stimulation of lumbar posterior roots, it is possible to evoke bilateral extension as well as rhythmic motor outputs. Epidural stimulation during treadmill stepping shows increased and/or modified motor activity. Finally, volitional efforts can alter epidurally induced rhythmic activities in incomplete spinal cord injury. Overall, we highlight that upper motor neuron paralysis does not entail complete absence of connectivity between cortex, brain stem, and spinal motor cells, but there can be altered anatomy and corresponding neurophysiological characteristics. With specific input to the spinal cord below the level of the lesion, the clinical status of upper motor neuron paralysis without structural modification can be modified, and movements can be initiated. Thus, external afferent input can partially replace brain control.

Multi-Electrode Array for Transcutaneous Lumbar Posterior Root Stimulation.

Interest in transcutaneous electrical stimulation of the lumbosacral spinal cord is increasing in human electrophysiological and clinical studies. The stimulation effects on lower limb muscles depend on the depolarization of segmentally organized posterior root afferents and, thus, the rostro-caudal stimulation site. In previous studies, selective stimulation was achieved by varying the positions of single self-adhesive electrodes over the thoracolumbar spine. Here, we developed a multi-electrode surface array consisting of 3 × 8 electrode pads and tested its stimulation-site specificity. The array was placed longitudinally over the spine covering the T10-L2 vertebrae. Two different hydrogel layer configurations were utilized: a single layer adhered to all electrode pads of the array and a configuration comprised of eight separate strips attached to the three transverse electrode pads of each level. Voltage measurements demonstrated that an effectively focused field distribution along the longitudinal extent of the array was not accomplished when using the single continuous hydrogel layer, and segmental selective stimulation of the posterior root afferents was not possible. The separate strips produced a focused electric field distribution at the rostro-caudal level of the electrode pads selected for stimulation. This configuration allowed for the preferential elicitation of posterior root-muscle reflexes in either the L2-L4 innervated quadriceps or the L5-S2 innervated triceps surae muscle groups. Such multi-electrode array for transcutaneous spinal cord stimulation shall allow for improved control of stimulation conditions in electrophysiological studies and time-dependent and site-specific stimulation patterns for neuromodulation applications.

Augmentation of Voluntary Locomotor Activity by Transcutaneous Spinal Cord Stimulation in Motor-Incomplete Spinal Cord-Injured Individuals.

The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control.

Sensory feedback and central neuronal interactions in mouse locomotion.

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyse a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behaviour to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

Non-canonical adrenergic neuromodulation of motoneuron intrinsic excitability through ß-receptors in wild-type and ALS mice.

Altered neuronal excitability and synaptic inputs to motoneurons are part of the pathophysiology of Amyotrophic Lateral Sclerosis. The cAMP/PKA pathway regulates both of them but therapeutic interventions at this level are limited by the lack of knowledge about suitable pharmacological entry points. Here we used transcriptomics on microdissected and in situ motoneurons to reveal the modulation of PKA-coupled receptorome in SOD1(G93A) ALS mice, vs WT, demonstrating the dysregulation of multiple PKA-coupled GPCRs, in particular on vulnerable MNs, and the relative sparing of ß-adrenergic receptors. In vivo MN electrophysiology showed that ß2/ß3 agonists acutely increase excitability, in particular the input/output relationship, demonstrating a non-canonical adrenergic neuromodulation mediated by ß2/ß3 receptors both in WT and SOD1 mice. The excitability increase corresponds to the upregulation of immediate-early gene expression and dysregulation of ion channels transcriptome. However the ß2/ß3 neuromodulation is submitted to a strong homeostasis, since a ten days delivery of ß2/ß3 agonists results in an abolition of the excitability increase. The homeostatic response is largely caused by a substantial downregulation of PKA-coupled GPCRs in MNs from WT and SOD1 mice. Thus, ß-adrenergic receptors are physiologically involved in the regulation of MN excitability and transcriptomics, but, intriguingly, a strong homeostatic response is triggered upon chronic pharmacologic intervention.

Investigating the roles of reflexes and central pattern generators in the control and modulation of human locomotion using a physiologically plausible neuromechanical model.

Objective.Studying the neural components regulating movement in human locomotion is obstructed by the inability to perform invasive experimental recording in the human neural circuits. Neuromechanical simulations can provide insights by modeling the locomotor circuits. Past neuromechanical models proposed control of locomotion either driven by central pattern generators (CPGs) with simple sensory commands or by a purely reflex-based network regulated by state-machine mechanisms, which activate and deactivate reflexes depending on the detected gait cycle phases. However, the physiological interpretation of these state machines remains unclear. Here, we present a physiologically plausible model to investigate spinal control and modulation of human locomotion.Approach.We propose a bio-inspired controller composed of two coupled CPGs that produce the rhythm and pattern, and a reflex-based network simulating low-level reflex pathways and Renshaw cells. This reflex network is based on leaky-integration neurons, and the whole system does not rely on changing reflex gains according to the gait cycle state. The musculoskeletal model is composed of a skeletal structure and nine muscles per leg generating movement in sagittal plane.Main results.Optimizing the open parameters for effort minimization and stability, human kinematics and muscle activation naturally emerged. Furthermore, when CPGs were not activated, periodic motion could not be achieved through optimization, suggesting the necessity of this component to generate rhythmic behavior without a state machine mechanism regulating reflex activation. The controller could reproduce ranges of speeds from 0.3 to 1.9 m s-1. The results showed that the net influence of feedback on motoneurons (MNs) during perturbed locomotion is predominantly inhibitory and that the CPGs provide the timing of MNs' activation by exciting or inhibiting muscles in specific gait phases.Significance.The proposed bio-inspired controller could contribute to our understanding of locomotor circuits of the intact spinal cord and could be used to study neuromotor disorders.

Distinct roles of spinal commissural interneurons in transmission of contralateral sensory information.

Crossed reflexes (CR) are mediated by commissural pathways transmitting sensory information to the contralateral side of the body, but the underlying network is not fully understood. Commissural pathways coordinating the activities of spinal locomotor circuits during locomotion have been characterized in mice, but their relationship to CR is unknown. We show the involvement of two genetically distinct groups of commissural interneurons (CINs) described in mice, V0 and V3 CINs, in the CR pathways. Our data suggest that the exclusively excitatory V3 CINs are directly involved in the excitatory CR, and show that they are essential for the inhibitory CR. In contrast, the V0 CINs, a population that includes excitatory and inhibitory CINs, are not directly involved in excitatory or inhibitory CRs but down-regulate the inhibitory CR. Our data provide insights into the spinal circuitry underlying CR in mice, describing the roles of V0 and V3 CINs in CR.

Sensory Feedback and Central Neuronal Interactions in Mouse Locomotion.

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyze a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behavior to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

Spinal control of locomotion before and after spinal cord injury.

Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore-hind coupling together with appropriate control of left-right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.

Distinct roles of spinal commissural interneurons in transmission of contralateral sensory information.

Crossed reflexes are mediated by commissural pathways transmitting sensory information to the contralateral side of the body, but the underlying network is not fully understood. Commissural pathways coordinating the activities of spinal locomotor circuits during locomotion have been characterized in mice, but their relationship to crossed reflexes is unknown. We show the involvement of two genetically distinct groups of commissural interneurons (CINs) described in mice, V0 and V3 CINs, in the crossed reflex pathways. Our data suggest that the exclusively excitatory V3 CINs are directly involved in the excitatory crossed reflexes and show that they are essential for the inhibitory crossed reflexes. In contrast, the V0 CINs, a population that includes excitatory and inhibitory CINs, are not directly involved in excitatory or inhibitory crossed reflexes but downregulate the inhibitory crossed reflexes. Our data provide insights into the spinal circuitry underlying crossed reflexes in mice, describing the roles of V0 and V3 CINs in crossed reflexes.

Spinal control of locomotion before and after spinal cord injury.

Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore-hind coupling together with appropriate control of left-right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.

The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice.

Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. The V3 neurons are known to be involved in interlimb coordination. We previously modeled the locomotor spinal circuitry controlling interlimb coordination (Danner et al., 2017). This model included the local V3 neurons that mediate mutual excitation between left and right rhythm generators (RGs). Here, our focus was on V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used a lateral-sequence walk. To reproduce this data and understand the functional roles of V3 aLPNs, we extended our previous model by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The extended model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left-right interactions within lumbar and cervical cords, promote left-right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.

Contribution of Afferent Feedback to Adaptive Hindlimb Walking in Cats: A Neuromusculoskeletal Modeling Study.

Mammalian locomotion is generated by central pattern generators (CPGs) in the spinal cord, which produce alternating flexor and extensor activities controlling the locomotor movements of each limb. Afferent feedback signals from the limbs are integrated by the CPGs to provide adaptive control of locomotion. Responses of CPG-generated neural activity to afferent feedback stimulation have been previously studied during fictive locomotion in immobilized cats. Yet, locomotion in awake, behaving animals involves dynamic interactions between central neuronal circuits, afferent feedback, musculoskeletal system, and environment. To study these complex interactions, we developed a model simulating interactions between a half-center CPG and the musculoskeletal system of a cat hindlimb. Then, we analyzed the role of afferent feedback in the locomotor adaptation from a dynamic viewpoint using the methods of dynamical systems theory and nullcline analysis. Our model reproduced limb movements during regular cat walking as well as adaptive changes of these movements when the foot steps into a hole. The model generates important insights into the mechanism for adaptive locomotion resulting from dynamic interactions between the CPG-based neural circuits, the musculoskeletal system, and the environment.

Can the human lumbar posterior columns be stimulated by transcutaneous spinal cord stimulation? A modeling study.

Stimulation of different spinal cord segments in humans is a widely developed clinical practice for modification of pain, altered sensation, and movement. The human lumbar cord has become a target for modification of motor control by epidural and, more recently, by transcutaneous spinal cord stimulation. Posterior columns of the lumbar spinal cord represent a vertical system of axons and when activated can add other inputs to the motor control of the spinal cord than stimulated posterior roots. We used a detailed three-dimensional volume conductor model of the torso and the McIntyre-Richard-Grill axon model to calculate the thresholds of axons within the posterior columns in response to transcutaneous lumbar spinal cord stimulation. Superficially located large-diameter posterior column fibers with multiple collaterals have a threshold of 45.4 V, three times higher than posterior root fibers (14.1 V). With the stimulation strength needed to activate posterior column axons, posterior root fibers of large and small diameters as well as anterior root fibers are coactivated. The reported results inform on these threshold differences, when stimulation is applied to the posterior structures of the lumbar cord at intensities above the threshold of large-diameter posterior root fibers.

Ipsi- and Contralateral Oligo- and Polysynaptic Reflexes in Humans Revealed by Low-Frequency Epidural Electrical Stimulation of the Lumbar Spinal Cord.

Epidural electrical stimulation (EES) applied over the human lumbosacral spinal cord provides access to afferent fibers from virtually all lower-extremity nerves. These afferents connect to spinal networks that play a pivotal role in the control of locomotion. Studying EES-evoked responses mediated through these networks can identify some of their functional components. We here analyzed electromyographic (EMG) responses evoked by low-frequency (2-6 Hz) EES derived from eight individuals with chronic, motor complete spinal cord injury. We identified and separately analyzed three previously undescribed response types: first, crossed reflexes with onset latencies of ~55 ms evoked in the hamstrings; second, oligosynaptic reflexes within 50 ms post-stimulus superimposed on the monosynaptic posterior root-muscle reflexes in the flexor muscle tibialis anterior, but with higher thresholds and no rate-sensitive depression; third, polysynaptic responses with variable EMG shapes within 50-450 ms post-stimulus evoked in the tibialis anterior and triceps surae, some of which demonstrated consistent changes in latencies with graded EES. Our observations suggest the activation of commissural neurons, lumbar propriospinal interneurons, and components of the late flexion reflex circuits through group I and II proprioceptive afferent inputs. These potential neural underpinnings have all been related to spinal locomotion in experimental studies.