Are interlimb interactions disturbed in patients with Parkinson’s disease? A study under unloading conditions

During natural human locomotion, neural connections are activated that are typical of regulation of the quadrupedal walking. The interaction between the neural networks generating rhythmic movements of the upper and lower limbs depends on tonic state of each of these networks regulated by motor signals from the brain. Distortion of these signals in patients with Parkinson’s disease (PD) may lead to disruption of the interlimb interactions. We examined the effect of movements of the limbs of one girdle on the parameters of the motor activity of another limb girdle at their joint cyclic movements under the conditions of arm and leg unloading in 17 patients with PD and 16 healthy subjects. We have shown that, in patients, the effect of voluntary and passive movements of arms, as well as the active movement of the distal parts of arms, on the voluntary movement of legs is weak, while in healthy subjects, the effect of arm movements on the parameters of voluntary stepping is significant. The effect of arm movements on the activation of the involuntary stepping by vibrational stimulation of-legs in patients was absent, while in healthy subjects, the motor activity of arms increased the possibility of involuntary rhythmic movements activation. Differences in the effect of leg movements on the rhythmic movements of arms were found in both patients and healthy subjects. The interlimb interaction appeared after drug administration. However, the effect of the drug was not sufficient for the recovery of normal state of the neural networks in patients. In PD patients, neural networks generating stepping rhythm have an increased tonic activity, which prevents the activation and appearance of involuntary rhythmic movements facilitating the effects of arms on legs.     

Genetic identification of spinal interneurons that coordinate left-right locomotor activity necessary for walking movements

The sequential stepping of left and right limbs is a fundamental motor behavior that underlies walking movements. This relatively simple locomotor behavior is generated by the rhythmic activity of motor neurons under the control of spinal neural networks known as central pattern generators (CPGs) that comprise multiple interneuron cell types. Little, however, is known about the identity and contribution of defined interneuronal populations to mammalian locomotor behaviors. We show a discrete subset of commissural spinal interneurons, whose fate is controlled by the activity of the homeobox gene Dbx1, has a critical role in controlling the left-right alternation of motor neurons innervating hindlimb muscles. Dbx1 mutant mice lacking these ventral interneurons exhibit an increased incidence of cobursting between left and right flexor/extensor motor neurons during drug-induced locomotion. Together, these findings identify Dbx1-dependent interneurons as key components of the spinal locomotor circuits that control stepping movements in mammals.     

Caterpillar crawling over irregular terrain: anticipation and local sensing

Animal locomotion is produced by co-coordinated patterns of motor activity that are generally organized by central pattern generators and modified by sensory feedback. Animals with remote sensing can anticipate obstacles and make adjustments in their gait to accommodate them. It is largely unknown how animals that rely on touch might use such information to adjust their gait. One possibility is immediate (reflexive) change in motor activity. Elongated animals, however, might modulate movements by passing information from anterior to posterior segments. Using the caterpillar Manduca sexta we examined the movements of the most anterior abdominal prolegs as they approached an obstacle. The first pair of prolegs anticipated the obstacle by lifting more quickly in the earliest part of the swing phase: the caterpillar had information about the obstacle at proleg lift-off. Sometimes the prolegs corrected their trajectory mid-step. Removal of sensory hairs on the stepping leg did not affect the early anticipatory movements, but did change the distance at which the mid-step corrections occurred. We conclude that anterior sensory information can be passed backwards and used to modulate an ongoing crawl. The local sensory hairs on each body segment can then fine-tune movements of the prolegs as they approach an obstacle.     

Kinematics of the Coordination of Pointing during Locomotion

In natural motor behaviour arm movements, such as pointing or reaching, often need to be coordinated with locomotion. The underlying coordination patterns are largely unexplored, and require the integration of both rhythmic and discrete movement primitives. For the systematic and controlled study of such coordination patterns we have developed a paradigm that combines locomotion on a treadmill with time-controlled pointing to targets in the three-dimensional space, exploiting a virtual reality setup. Participants had to walk at a constant velocity on a treadmill. Synchronized with specific foot events, visual target stimuli were presented that appeared at different spatial locations in front of them. Participants were asked to reach these stimuli within a short time interval after a “go” signal. We analysed the variability patterns of the most relevant joint angles, as well as the time coupling between the time of pointing and different critical timing events in the foot movements. In addition, we applied a new technique for the extraction of movement primitives from kinematic data based on anechoic demixing. We found a modification of the walking pattern as consequence of the arm movement, as well as a modulation of the duration of the reaching movement in dependence of specific foot events. The extraction of kinematic movement primitives from the joint angle trajectories exploiting the new algorithm revealed the existence of two distinct main components accounting, respectively, for the rhythmic and discrete components of the coordinated movement pattern. Summarizing, our study shows a reciprocal pattern of influences between the coordination patterns of reaching and walking. This pattern might be explained by the dynamic interactions between central pattern generators that initiate rhythmic and discrete movements of the lower and upper limbs, and biomechanical factors such as the dynamic gait stability.     

Application of the mathematics of coupled oscillator systems to the analysis of the neural control of locomotion.

In many animals, the activities of limb motor neurons are rhythmic during locomotion. In some animals it is known that each limb is innervated by a local control center that resides in a discrete portion of the central nervous system. Each local control center is a biological oscillator. Since each limb moves with the same frequency as each other limb and with regulated phase delay with respect to each other limb, then it follows that the local control centers are coupled to one another. The locomotory pattern generator within the central nervous system is therefore a coupled oscillator system. The mathematics of coupled oscillator systems can assist in the construction of a model of the neural pattern generator. This model can be utilized to formulate testable predictions concerning the neural control of locomotion. Experimental data gathered from organisms in several phylums are consistent with the predictions of the model.     

Visuomotor coordination in locomotion.

This article reviews the recent literature concerning the role of visual information in the control of locomotion with an emphasis on the neurophysiological mechanisms that underlie visually triggered, voluntary, gait modifications. Data are presented to show how these gait modifications may be encoded by the motor cortex, and how they may interact with the basic locomotor rhythm.     

Modular neuromuscular control of human locomotion by central pattern generator

The central pattern generators (CPG) in the spinal cord are thought to be responsible for producing the rhythmic motor patterns during rhythmic activities. For locomotor tasks, this involves much complexity, due to a redundant system of muscle actuators with a large number of highly nonlinear muscles. This study proposes a reduced neural control strategy for the CPG, based on modular organization of the co-active muscles, i.e., muscle synergies. Four synergies were extracted from the EMG data of the major leg muscles of two subjects, during two gait trials each, using non-negative matrix factorization algorithm. A Matsuoka׳s four-neuron CPG model with mutual inhibition, was utilized to generate the rhythmic activation patterns of the muscle synergies, using the hip flexion angle and foot contact force information from the sensory afferents as inputs. The model parameters were tuned using the experimental data of one gait trial, which resulted in a good fitting accuracy (RMSEs between 0.0491 and 0.1399) between the simulation and experimental synergy activations. The model׳s performance was then assessed by comparing its predictions for the activation patterns of the individual leg muscles during locomotion with the relevant EMG data. Results indicated that the characteristic features of the complex activation patterns of the muscles were well reproduced by the model for different gait trials and subjects. In general, the CPG- and muscle synergy-based model was promising in view of its simple architecture, yet extensive potentials for neuromuscular control, e.g., resolving redundancies, distributed and fast control, and modulation of locomotion by simple control signals.     

Self-organized control of bipedal locomotion by neural oscillators in unpredictable environment

A new principle of sensorimotor control of legged locomotion in an unpredictable environment is proposed on the basis of neurophysiological knowledge and a theory of nonlinear dynamics. Stable and flexible locomotion is realized as a global limit cycle generated by a global entrainment between the rhythmic activities of a nervous system composed of coupled neural oscillators and the rhythmic movements of a musculo-skeletal system including interaction with its environment. Coordinated movements are generated not by slaving to an explicit representation of the precise trajectories of the movement of each part but by dynamic interactions among the nervous system, the musculo-skeletal system and the environment. The performance of a bipedal model based on the above principle was investigated by computer simulation. Walking movements stable to mechanical perturbations and to environmental changes were obtained. Moreover, the model generated not only the walking movement but also the running movement by changing a single parameter nonspecific to the movement. The transitions between the gait patterns occurred with hysteresis.     

Dominance of local sensory signals over inter-segmental effects in a motor system: experiments

Legged locomotion requires that information local to one leg, and inter-segmental signals coming from the other legs are processed appropriately to establish a coordinated walking pattern. However, very little is known about the relative importance of local and inter-segmental signals when they converge upon the central pattern generators (CPGs) of different leg joints. We investigated this question on the CPG of the middle leg coxa?Ctrochanter (CTr)-joint of the stick insect which is responsible for lifting and lowering the leg. We used a semi-intact preparation with an intact front leg stepping on a treadmill, and simultaneously stimulated load sensors of the middle leg. We found that middle leg load signals induce bursts in the middle leg depressor motoneurons (MNs). The same local load signals could also elicit rhythmic activity in the CPG of the middle leg CTr-joint when the stimulation of middle leg load sensors coincided with front leg stepping. However, the influence of front leg stepping was generally weak such that front leg stepping alone was only rarely accompanied by switching between middle leg levator and depressor MN activity. We therefore conclude that the impact of the local sensory signals on the levator?Cdepressor motor system is stronger than the inter-segmental influence through front leg stepping.     

Possible involvement of central pacemakers in clinical disorders of movement.

This review considers the evidence for possible involvement of central nervous system pacemaker neurons in several clinical disorders of movement. Two basic types of tremor are discussed from this point of view, i.e., 4--7/sec parkinsonian tremor, of possible thalamocortical origin, and 7--11/sec essential tremor of possible olivo-cerebellar origin. The importance of motor programs and abnormalities in their utilization are considered with reference to the loss of motor function in parkinsonism (? loss of motor programs), and the inappropriate release of such programs as a possible basis for the involuntary movements seen in other movement disorders, such as chorea, athetosis, dystonia, and hemiballismus. The possible role of pacemaker neurons controlling such programs is considered. Finally, the subject of locomotion and the pacemaker model of the spinal locomotor pattern generator for stepping are considered in relation to clinical disorders of gait. While critical evidence is lacking for pacemaker inovlvement in any of these disorders, their possible role is emphasized.     

Evaluating functional roles of phase resetting in generation of adaptive human bipedal walking with a physiologically based model of the spinal pattern generator

The central pattern generators (CPGs) in the spinal cord strongly contribute to locomotor behavior. To achieve adaptive locomotion, locomotor rhythm generated by the CPGs is suggested to be functionally modulated by phase resetting based on sensory afferent or perturbations. Although phase resetting has been investigated during fictive locomotion in cats, its functional roles in actual locomotion have not been clarified. Recently, simulation studies have been conducted to examine the roles of phase resetting during human bipedal walking, assuming that locomotion is generated based on prescribed kinematics and feedback control. However, such kinematically based modeling cannot be used to fully elucidate the mechanisms of adaptation. In this article we proposed a more physiologically based mathematical model of the neural system for locomotion and investigated the functional roles of phase resetting. We constructed a locomotor CPG model based on a two-layered hierarchical network model of the rhythm generator (RG) and pattern formation (PF) networks. The RG model produces rhythm information using phase oscillators and regulates it by phase resetting based on foot-contact information. The PF model creates feedforward command signals based on rhythm information, which consists of the combination of five rectangular pulses based on previous analyses of muscle synergy. Simulation results showed that our model establishes adaptive walking against perturbing forces and variations in the environment, with phase resetting playing important roles in increasing the robustness of responses, suggesting that this mechanism of regulation may contribute to the generation of adaptive human bipedal locomotion.     

Interactions between cognitive and sensory load while planning and controlling complex gait adaptations in Parkinson’s disease

Background

Recent research has argued that removal of relevant sensory information during the planning and control of simple, self-paced walking can result in increased demand on central processing resources in Parkinson’s disease (PD). However, little is known about more complex gait tasks that require planning of gait adaptations to cross over an obstacle in PD.

Methods

In order to understand the interaction between availability of visual information relevant for self-motion and cognitive load, the current study evaluated PD participants and healthy controls while walking toward and stepping over an obstacle in three visual feedback conditions: (i) no visual restrictions; (ii) vision of the obstacle and their lower limbs while in complete darkness; (iii) vision of the obstacle only while in complete darkness; as well as two conditions including a cognitive load (with a dual task versus without a dual task). Each walk trial was divided into an early and late phase to examine changes associated with planning of step adjustments when approaching the obstacle.

Results

Interactions between visual feedback and dual task conditions during the obstacle approach were not significant. Patients with PD had greater deceleration and step time variability in the late phase of the obstacle approach phase while walking in both dark conditions compared to control participants. Additionally, participants with PD had a greater number of obstacle contacts when vision of their lower limbs was not available specifically during the dual task condition. Dual task performance was worse in PD compared to healthy control participants, but notably only while walking in the dark regardless of visual feedback.

Conclusions

These results suggest that reducing visual feedback while approaching an obstacle shifts processing to somatosensory feedback to guide movement which imposes a greater demand on planning resources. These results are key to fully understanding why trips and falls occur in those with PD.

     

A two compartment model of the stepping generator: Analysis of the roles of a stage-setter and a rhythm generator

Recent studies on locomotion of the mesencephalic cat demonstrated that activation of the spinal stepping generator and the postural control system are dependent phenomena (Mori et al., 1978, 1980). This has motivated the construction of a new model of the stepping generator to account for interactions with the postural control system. The present model consists of two main compartments, the rhythm generator and the stage-setter. The rhythm generator generates rhythmic bursting discharges of extensor and flexor alpha motoneurons. The function of the stage-setter is to set and reset the excitability of extensor alpha motoneuron to a number of desired levels. This study analyzes interactions in this model between rhythm generating and postural control system. By adding a concept of stage-setting to the rhythm generator model, we succeed in simulating a variety of locomotor patterns observed in the mesencephalic cat, including stepping automatism (Mori et al., 1979).     

Enhanced locomotion caused by loss of the Drosophila DEG/ENaC protein Pickpocket1

Coordination of rhythmic locomotion depends upon a precisely balanced interplay between central and peripheral control mechanisms. Although poorly understood, peripheral proprioceptive mechanosensory input is thought to provide information about body position for moment-to-moment modifications of central mechanisms mediating rhythmic motor output. Pickpocket1 (PPK1) is a Drosophila subunit of the epithelial sodium channel (ENaC) family displaying limited expression in multiple dendritic (md) sensory neurons tiling the larval body wall and a small number of bipolar neurons in the upper brain. ppk1 null mutant larvae had normal external touch sensation and md neuron morphology but displayed striking alterations in crawling behavior. Loss of PPK1 function caused an increase in crawling speed and an unusual straight path with decreased stops and turns relative to wild-type. This enhanced locomotion resulted from sustained peristaltic contraction wave cycling at higher frequency with a significant decrease in pause period between contraction cycles. The mutant phenotype was rescued by a wild-type PPK1 transgene and duplicated by expressing a ppk1RNAi transgene or a dominant-negative PPK1 isoform. These results demonstrate that the PPK1 channel plays an essential role in controlling rhythmic locomotion and provide a powerful genetic model system for further analysis of central and peripheral control mechanisms and their role in movement disorders.     

The discontinuous nature of motor execution II. Merging discrete and rhythmic movements in a single-joint system -- the phase entrainment effect

 Initiation of rapid discrete flexion movements is significantly altered when a secondary rhythmic movement is performed simultaneously with the same limb; the onset of a stimulus-evoked discrete movement tends to occur time-locked to the oscillation: i.e., the rhythmic movement entrains the discrete response. This nonlinear interaction may reflect a specific principle of coordination of motor tasks which are simultaneously executed with the same effector. This part II of a tripartite research report on such single-muscle multiple-task coordination investigates the contribution of the dynamic properties of the muscle and its reflex circuitry to phase entrainment. Assuming a simple threshold-linear relationship between the control signals generated by the central nervous system and the observable kinematic and electromyographic signals, a secondary rhythmic movement will cause an additional phase-dependent delay between the central “go” command and the first observable change in actual kinematics of the compound movement. Several indicators for such threshold-linear interaction are derived and tested on real data obtained in psychophysical experiments. Four healthy subjects performed rapid lateral abductions of the index finger in response to a visual “go” signal. During a portion of the experiments, subjects produced additional low-amplitude oscillatory movements before stimulus presentation with either the same finger (one-handed task), or with the index finger of the other hand (two-handed task). Results showed phase entrainment and modulation of reaction times when the cyclic and the discrete movements were simultaneously executed by the same finger. But there was no entrainment in the bimanual execution of the tasks. The model was capable of reproducing the observed effects. It is concluded that coordination of voluntary movements which are concurrently performed by the same effector involves specific discontinuous operations, which represents an essential part of the mechanism of motor coordination. Phase entrainment reflects this characteristic discontinuous behavior of the lower stages of motor execution and does not necessarily require nonlinear interaction of motor commands at higher levels of motor processing. Received: 5 September 2001 / Accepted in revised form: 19 December 2001     

Neural coupling between upper and lower limbs during recumbent stepping.

During gait rehabilitation, therapists or robotic devices often supply physical assistance to a patient's lower limbs to aid stepping. The expensive equipment and intensive manual labor required for these therapies limit their availability to patients. One alternative solution is to design devices where patients could use their upper limbs to provide physical assistance to their lower limbs (i.e., self-assistance). To explore potential neural effects of coupling upper and lower limbs, we investigated neuromuscular recruitment during self-driven and externally driven lower limb motion. Healthy subjects exercised on a recumbent stepper using different combinations of upper and lower limb exertions. The recumbent stepper mechanically coupled the upper and lower limbs, allowing users to drive the stepping motion with upper and/or lower limbs. We instructed subjects to step with 1) active upper and lower limbs at an easy resistance level (active arms and legs); 2) active upper limbs and relaxed lower limbs at easy, medium, and hard resistance levels (self-driven); and 3) relaxed upper and lower limbs while another person drove the stepping motion (externally driven). We recorded surface electromyography (EMG) from six lower limb muscles. Self-driven EMG amplitudes were always higher than externally driven EMG amplitudes (P < 0.05). As resistance and upper limb exertion increased, self-driven EMG amplitudes also increased. EMG bursts during self-driven and active arms and legs stepping occurred at similar times. These results indicate that active upper limb movement increases neuromuscular activation of the lower limbs during cyclic stepping motions. Neurologically impaired humans that actively engage their upper limbs during gait rehabilitation may increase neuromuscular activation and enhance activity-dependent plasticity.     

Possible contributions of CPG activity to the control of rhythmic human arm movement

There is extensive modulation of cutaneous and H-reflexes during rhythmic leg movement in humans. Mechanisms controlling reflex modulation (e.g., phase- and task-dependent modulation, and reflex reversal) during leg movements have been ascribed to the activity of spinal central pattern generating (CPG) networks and peripheral feedback. Our working hypothesis has been that neural mechanisms (i.e., CPGs) controlling rhythmic movement are conserved between the human lumbar and cervical spinal cord. Thus reflex modulation during rhythmic arm movement should be similar to that for rhythmic leg movement. This hypothesis has been tested by studying the regulation of reflexes in arm muscles during rhythmic arm cycling and treadmill walking. This paper reviews recent studies that have revealed that reflexes in arm muscles show modulation within the movement cycle (e.g., phase-dependency and reflex reversal) and between static and rhythmic motor tasks (e.g., task-dependency). It is concluded that reflexes are modulated similarly during rhythmic movement of the upper and lower limbs, suggesting similar motor control mechanisms. One notable exception to this pattern is a failure of contralateral arm movement to modulate reflex amplitude, which contrasts directly with observations from the leg. Overall, the data support the hypothesis that CPG activity contributes to the neural control of rhythmic arm movement.     

Central pattern generating networks in insect locomotion

Central pattern generators (CPGs) are neural circuits that based on their connectivity can generate rhythmic and patterned output in the absence of rhythmic external inputs. This property makes CPGs crucial elements in the generation of many kinds of rhythmic motor behaviors in insects, such as flying, walking, swimming, or crawling. Arguably representing the most diverse group of animals, insects utilize at least one of these types of locomotion during one stage of their ontogenesis. Insects have been extensively used to study the neural basis of rhythmic motor behaviors, and particularly the structure and operation of CPGs involved in locomotion. Here, we review insect locomotion with regard to flying, walking, and crawling, and we discuss the contribution of central pattern generation to these three forms of locomotion. In each case, we compare and contrast the topology and structure of the CPGs, and we point out how these factors are involved in the generation of the respective motor pattern. We focus on the importance of sensory information for establishing a functional motor output and we indicate behavior‐specific adaptations. Furthermore, we report on the mechanisms underlying coordination between different body parts. Last but not least, by reviewing the state‐of‐the‐art knowledge concerning the role of CPGs in insect locomotion, we endeavor to create a common ground, upon which future research in the field of motor control in insects can build.     

A model of the neuro-musculo-skeletal system for human locomotion

The generation of human locomotion was examined by linking computational neuroscience with biomechanics from the perspective of nonlinear dynamical theory. We constructed a model of human locomotion, which includes a musculo-skeletal system with 8 segments and 20 muscles, a neural rhythm generator composed of 7 pairs of neural oscillators, and mechanisms for processing and transporting sensory and motor signals. Using a computer simulation, we found that locomotion emerged as a stable limit cycle that was generated by the global entrainment between the musculo-skeletal system, the neural system, and the environment. Moreover, the walking movements of the model could be compared quantitatively with those of experimental studies in humans.Part of this paper was presented to IVth International Symposium on Computer Simulation in Biomechanics, Paris, France, July 1, 1993