Locomotor Control Systems Research Articles

Magnitude Estimates Orchestrate Hierarchal Construction of Context-Dependent Representational Maps for Vestibular Space and Time: Theoretical Implications for Functional Dizziness.

Maintaining balance necessitates an accurate perceptual map of the external world. Neuro-physiological mechanisms of locomotor control, sensory perception, and anxiety systems have been viewed as separate entities that can on occasion affect each other (i.e., walking on ice). Emerging models are more integrated, that envision sensory perception and threat assessment as a fundamental component of balance. Here we present an empirically based theoretical argument that vestibular cortical areas construct magnitude estimates of our environment via neural integration of incoming sensory signals. In turn, these cortically derived magnitude estimates, construct context-dependent vestibulo-spatial and vestibulo-temporal, representational maps of the external world, and ensure an appropriate online scaling factor for associated action-perceptual risk. Thus, threat signals are able to exert continuous influence on planning movements, predicting outcomes of motion of self and surrounding objects, and adjusting tolerances for discrepancies between predicted and actual estimates. Such a process affects the degree of conscious attention directed to spatial and temporal aspects of motion stimuli, implying that maintaining balance may follow a Bayesian approach in which the relative weighting of vestibulo-spatial and vestibulo-temporal signals and tolerance for discrepancies are adjusted in accordance with the level of threat assessment. Here, we seek to mechanistically explain this process with our novel empirical concept of a Brainstem Cortical Scaling Metric (BCSM), which we developed from a series of neurophysiological studies illustrating the central role of interhemispheric vestibulo-cortical asymmetries for balance control. We conclude by using the BCSM to derive theoretical predictions of how a dysfunctional BCSM can mechanistically account for functional dizziness.

Hypothalamic Pomc Neurons Innervate the Spinal Cord and Modulate the Excitability of Premotor Circuits

Locomotion requires energy, yet animals need to increase locomotion in order to find and consume food in energy-deprived states. While such energy homeostatic coordination suggests brain origin, whether the central melanocortin 4 receptor (Mc4r) system directly modulates locomotion through motor circuits is unknown. Here, we report that hypothalamic Pomc neurons in zebrafish and mice have long-range projections into spinal cord regions harboring Mc4r-expressing V2a interneurons, crucial components of the premotor networks. Furthermore, in zebrafish, Mc4r activation decreases the excitability of spinal V2a neurons as well as swimming and foraging, while systemic or V2a neuron-specific blockage of Mc4r promotes locomotion. In contrast, in mice, electrophysiological recordings revealed that two-thirds of V2a neurons in lamina X are excited by the Mc4r agonist α-MSH, and acute inhibition of Mc4r signaling reduces locomotor activity. In addition, we found other Mc4r neurons in spinal lamina X that are inhibited by α-MSH, which is in line with previous studies in rodents where Mc4r agonists reduced locomotor activity. Collectively, our studies identify spinal V2a interneurons as evolutionary conserved second-order neurons of the central Mc4r system, providing a direct anatomical and functional link between energy homeostasis and locomotor control systems. The net effects of this modulatory system on locomotor activity can vary between different vertebrate species and, possibly, even within one species. We discuss the biological sense of this phenomenon in light of the ambiguity of locomotion on energy balance and the different living conditions of the different species.

Simultaneous low-frequency deep brain stimulation of the substantia nigra pars reticulata and high-frequency stimulation of the subthalamic nucleus to treat levodopa unresponsive freezing of gait in Parkinson's disease: A pilot study

IntroductionExperimental studies suggest that low-frequency (LF) (63 Hz) deep brain stimulation (DBS) of the substantia nigra pars reticulata (SNr) could be useful to regulate gait disorders refractory to medical treatment in Parkinson's disease (PD). The SNr neurons could act as high-frequency (HF) pacemakers within locomotor control systems. Currently, no specific therapies can treat gait disorders in PD with insufficient response to dopaminergic treatment. ObjectiveTo investigate whether LF-SNr-DBS combined with standard HF stimulation of the subthalamic nucleus (STN) is clinically relevant in improving gait disorders that no longer respond to levodopa in PD patients, compared with HF-STN or LF-SNr stimulation alone. MethodsPatients received LF-SNr or HF-STN stimulation alone or combined (COMB) stimulation of both nuclei (crossover design). The nucleus to be stimulated was randomly assigned and clinical evaluations performed by a blinded examiner after three months follow-up for each. Clinical assessment included the Freezing of Gait questionnaire, Tinetti Balance and Walking Assessing tool, and Unified Parkinson's Disease Rating. ResultsWe included six patients (mean age 59.1 years, disease duration 16.1 years). All patients suffered motor fluctuations and dyskinesias. The best results were obtained with COMB in four patients (who preferred and remained with COMB over 3 years of follow-up) and with HF-STN in two patients. SNr stimulation alone did not produce better results than COMB or STN in any patient. ConclusionCOMB and HF-STN stimulation improved PD-associated gait disorders in this preliminary case series, sustained over time. Further multicenter investigations are required to better explore this therapeutic option.

Chapter 1 - Sensorimotor anatomy of gait, balance, and falls

The review demonstrates that control of posture and locomotion is provided by systems across the caudal-to-rostral extent of the neuraxis. A common feature of the neuroanatomic organization of the postural and locomotor control systems is the presence of key nodes for convergent input of multisensory feedback in conjunction with efferent copies of the motor command. These nodes include the vestibular and reticular nuclei and interneurons in the intermediate zone of the spinal cord (Rexed's laminae VI-VIII). This organization provides both spatial and temporal coordination of the various goals of the system and ensures that the large repertoire of voluntary movements is appropriately coupled to either anticipatory or reactive postural adjustments that ensure stability and provide the framework to support the intended action. Redundancies in the system allow adaptation and compensation when sensory modalities are impaired. These alterations in behavior are learned through reward- and error-based learning processes implemented through basal ganglia and cerebellar pathways respectively. However, neurodegenerative processes or lesions of these systems can greatly compromise the capacity to sufficiently adapt and sometimes leads to maladaptive changes that impair movement control. When these impairments occur, the risk of falls can be significantly increased and interventions are required to reduce morbidity.

The structure and function of the dopamine transporter and its role in CNS diseases.

In this chapter, we explore the basic science of the dopamine transporter (DAT), an integral component of a system that regulates dopamine homeostasis. Dopamine is a key neurotransmitter for several brain functions including locomotor control and reward systems. The transporter structure, function, mechanism of action, localization, and distribution, in addition to gene regulation, are discussed. Over many years, a wealth of information concerning the DAT has been accrued and has led to increased interest in the role of the DAT in a plethora of central nervous system diseases. These DAT characteristics are explored in relation to a range of neurological and neuropsychiatric diseases, with a particular focus on the genetics of the DAT. In addition, we discuss the pharmacology of the DAT and how this relates to disease and addiction.

A Silicon Central Pattern Generator Controls Locomotion in Vivo

We present a neuromorphic silicon chip that emulates the activity of the biological spinal central pattern generator (CPG) and creates locomotor patterns to support walking. The chip implements ten integrate-and-fire silicon neurons and 190 programmable digital-to-analog converters that act as synapses. This architecture allows for each neuron to make synaptic connections to any of the other neurons as well as to any of eight external input signals and one tonic bias input. The chip's functionality is confirmed by a series of experiments in which it controls the motor output of a paralyzed animal in real-time and enables it to walk along a three-meter platform. The walking is controlled under closed-loop conditions with the aide of sensory feedback that is recorded from the animal's legs and fed into the silicon CPG. Although we and others have previously described biomimetic silicon locomotor control systems for robots, this is the first demonstration of a neuromorphic device that can replace some functions of the central nervous system in vivo.

Adaptive control of gait stability in reducing slip-related backward loss of balance

The properties of adaptation within the locomotor and balance control systems directed towards improving one's recovery strategy for fall prevention are not well understood. The purpose of this study was to examine adaptive control of gait stability to repeated slip exposure leading to a reduction in backward loss of balance (and hence in protective stepping). Fourteen young subjects experienced a block of slips during walking. Pre- and post-slip onset stability for all slip trials was obtained as the shortest distance at touchdown (slipping limb) and lift-off (contralateral limb), respectively, between the measured center of mass (COM) state, that is, position and velocity relative to base of support (BOS) and the mathematically predicted threshold for backward loss of balance. An improvement in pre- and post-slip onset stability correlated with a decrease in the incidence of balance loss from 100% (first slip) to 0% (fifth slip). While improvements in pre-slip stability were affected by a proactive anterior shift in COM position, the significantly greater post-slip onset improvements resulted from reductions in BOS perturbation intensity. Such reactive changes in BOS perturbation intensity resulted from a reduction in the demand on post-slip onset braking impulse, which was nonetheless influenced by the proactive adjustments in posture and gait pattern (e.g., the COM position, step length, flat foot landing and increased knee flexion) prior to slip onset. These findings were indicative of the maturing process of the adaptive control. This was characterized by a shift from a reliance on feedback control for postural correction to being influenced by feedforward control, which improved pre-slip stability and altered perturbation intensity, leading to skateover or walkover (>0.05 m or <0.05 m displacement, respectively) adaptive strategies. Finally, the stability at contralateral limb lift-off was highly predictive of balance loss occurrence and its subsequent rapid reduction, supporting the notion of the internal representations of stability limits that could be modified and updated, as a key component in the adaptive control.

Dopamine transporter: basic science and human variation of a key molecule for dopaminergic function, locomotion, and parkinsonism.

We review the basic science of the dopamine transporter (DAT), a key neurotransmitter for locomotor control and reward systems, including those lost or deranged in Parkinson's disease (PD). Physiology, pharmaceutical features, expression, cDNA, protein structure/function relationships, and phosphorylation and regulation are discussed. The localization of DAT provides the best marker for the integrity of just the pre-synaptic dopaminergic systems that are most affected in PD. Its function is key for the actions of several toxins that provide some of the best current models for idiopathic parkinsonism, and its variation can clearly alter movement. The wealth of information about this interesting molecule that has been developed over the last 12 years has led to increased interest in DAT among workers interested in both normal and abnormal movement.

How animals move: an integrative view.

Recent advances in integrative studies of locomotion have revealed several general principles. Energy storage and exchange mechanisms discovered in walking and running bipeds apply to multilegged locomotion and even to flying and swimming. Nonpropulsive lateral forces can be sizable, but they may benefit stability, maneuverability, or other criteria that become apparent in natural environments. Locomotor control systems combine rapid mechanical preflexes with multimodal sensory feedback and feedforward commands. Muscles have a surprising variety of functions in locomotion, serving as motors, brakes, springs, and struts. Integrative approaches reveal not only how each component within a locomotor system operates but how they function as a collective whole.

Basic Neurophysiology of Primate Locomotion

To initiate and terminate bipedal and quadrupedal locomotor movements, a smooth transition to and from standing is necessary. For this, integration of postural and locomotor control systems is required. Recent studies in nonhuman primates and other quadrupedal animals such as cats have clearly shown that there exist significant analogies between the primate species investigated (Macaca mulatta, Macaca fascicularis, and marmosets) and the cats regarding the spinal stepping generator or central pattern generator (CPG), supraspinal descending pathways which activate CPG, and the midbrain and brain stem postural and locomotor control structures. Further studies aimed at elucidating the differences and similarities in the manner of locomotor control among different animal species will help us in understanding the control mechanisms involved in both bipedal and quadrupedal locomotor movements in nonhuman primates.

Development of NADPH diaphorase-positive pedunculopontine nucleus neurons

Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry was used to localize cholinergic neurons in the pedunculopontine nucleus of neonatal and adult rats. Measurements of cell body areas revealed an average area around 200 μm 2 at birth, followed by a significant increase to approximately 500 μm 2 by 2 weeks of age. Thereafter, there was a decrease in cell area such that by 5 weeks of age the neurons had attained their adult size of around 300 μm 2. The marked increase in cell size at the end of 2 weeks of age is discussed in relation to significant events in the development of locomotor and other rhythmic function control systems.

Contribution of postural muscle tone to full expression of posture and locomotor movements: Multi-faceted analyses of its setting brainstem-spinal cord mechanisms in the cat.

In this minireview, I have summarized and discussed our results concerning the neuronal mechanisms of postural suppression, and our thoughts about contribution of postural muscle tone to the full expression of locomotion. The identified brainstem-spinal cord system is schematically illustrated in Fig. 1 with its neuronal constituents (A). When cells of origin of this system (cells in the nucleus reticularis pontis oralis), or the pathway descending from these cells (DTF area) are tonically activated, cells in the nucleus reticularis gigantocellularis (gc cells) are also tonically activated, and with this process the system as a whole exerts generalized or non-reciprocal tonic inhibitory effects upon alpha-motoneurons innervating hindlimb extensor and flexor muscles. In consequence, postural muscle tone, especially that of the hindlimbs, is tonically suppressed and results in sustained suppression of postural support both in acute decerebrate cats (locomotor preparation) and in awake, freely moving cats, terminating locomotor movements. Since postural control and locomotor control are not separate phenomena, our results indicate that interaction of the above-described two control systems should be studied at each level of the brainstem and the spinal cord. In fact, contribution of brainstem neurons and of spinal interneurons has already been studied. It may also be interesting to elucidate supra-pontine structures which activate the identified brainstem-spinal cord inhibitory system. Such a study may elucidate the neuronal structures related not only to the termination of on going movements but also to the muscular atonia observed during active sleep. As demonstrated, even for the understanding of the brainstem-spinal cord system involved in postural suppression, multi-faceted and mutally related analytical approaches have been necessary as suggested by Brookhart, and these approaches allowed us to approach a much better understanding of the problem one faces. They were neuroanatomical analyses of plausible neuronal structures, electrophysiological analyses of their synaptic organizations, the neuropharmacological analyses of their putative neurotransmitters, and finally the most important, behavioral analyses. For a thorough understanding of the dynamics of postural and locomotor control systems, the problems we are now concerned with are to identify both the "hardware" and the "software" of these two systems. Understanding of the hardware requires an elucidation of the neuronal circuits including synaptic organizations, and that of the software an identification of the putative neurotransmitters that set the identified neuronal circuit to work, so that the systems as a whole exhibit a meaningful external manifestation.(ABSTRACT TRUNCATED AT 400 WORDS)

In vitro brainstem-spinal cord preparations for study of motor systems for mammalian respiration and locomotion

Recently developed in vitro preparations of the brainstem-spinal cord from neonatal rat suitable for investigation of motor control systems for mammalian locomotion and respiration are described. The preparations remain viable for extended periods under standard in vitro conditions and generate rhythmic motor patterns for locomotion and respiration. The methodology of the preparations and characteristics of the motor output patterns are described. The preparations retain functional circuitry for major components of the motor control systems, including brainstem respiratory and spinal locomotor pattern generating networks, brainstem locomotor command regions, descending bulbospinal and ascending spinal pathways, and mechanosensory afferent input systems. They therefore offer potential for investigation of diverse aspects of the mammalian respiratory and locomotor control systems.