Novel method for activation of the locomotor circuitry in human

We examine the possibility for activation of the involuntary locomotion of the lower limbs by spinal electromagnetic stimulation (ES). The subject laid on the left side. The legs are supported in a gravity-neutral position by special mounting that to provide horizontal rotation in the hip, knee and ankle. ES (3 Hz and 1.56 Tesla) at the T11,-T12 vertebrae induced involuntary locomotor-like movements in the legs. The latency from the initiation of ES to the first EMG burst compoused 0.68 +/- 1.0 s and it shortened at increasing of the frequency ES from 3 Hz to 20 Hz. Thus, the spinal ES can unduce the activation of the locomotor movements in human.     

Noninvasive insulin delivery systems

The review considers commercial insulin formulations. Special attention is paid to difficulties and strategies of the development of alternative hormone delivery systems (buccal, transdermal, intranasal, pulmonary and oral). At the moment there is only one approved formulation of the noninvasive insulin in the world.     

Investigation of spinal neuronal mechanisms of movement control systems

Morphological and electrophysiological investigations of the means whereby the principal descending motor systems (the cortico-, rubro-, reticulo-, and vestibulo-spinal tracts) are connected with the segmental interneuronal apparatus and motoneurons show that these connections can be based on two different principles. Descending systems either activate motoneurons directly (monosynaptically) or are connected primarily with various interneuron systems, exerting their influence in that case by regulating the activity of simpler or more complex spinal mechanisms. The older descending system (reticulo- and vestibulo-spinal) possess a monosynaptic excitatory action of motoneurons; the evolutionarily newer descending systems, which transmit the most complex motor signals from the cerebral and cerebellar cortex to the spinal cord (cortico- and rubro-spinal), terminate synaptically in every case on interneurons. It is only in primates that a few cortico-spinal fibers form monosynaptic connections with motoneurons. The chief ways of action of the descending systems on interneurons are: control of the afferent inflow into the interneuron system by presynaptic inhibition of the corresponding synapses; control of the interneuron system by postsynaptic interaction with afferent influences; control of motoneurons through the specialized interneuron apparatus. The investigation shows that the last of these mechanisms functions in the cortico- and rubro-spinal, and possibly also in the reticulo- and vestibulo-spinal systems. The functional role of the various means of connection of the descending systems with the spinal neurons in the system of movement control is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 2, No. 2, pp. 189–202, March–April, 1970.     

Transcutaneous electrical stimulation of the spinal cord: non-invasive tool for activation of locomotor circuitry in human

A new tool for locomotor circuitry activation in the non-injured human by transcutaneous electrical spinal cord stimulation (tSCS) has been described. We show that continuous tSCS over T11-T12 vertebrae at 5-40 Hz induced involuntary locomotor-like stepping movements in subjects with their legs in a gravity-independent position. The increase of frequency of tSCS from 5 to 30 Hz augmented the amplitude of evoked stepping movements. The duration of cycle period did not depend on frequency of tSCS. During tSCS the hip, knee and ankle joints were involved in the stepping performance. It has been suggested that tSCS activates the locomotor circuitry through the dorsal roots. It appears that tSCS can be used as a non-invasive method in rehabilitation of spinal pathology.     

Morphological study of the origin of spinal locomotor strip fibers

The origin of spinal locomotor strip fibers was investigated in cats by applying electrical stimulation and the retrograde axonal horseradish peroxidase transport technique. It was found to be mainly composed of corticospinal tract fibers. Moderate numbers of reticulospinal tract and trigeminal spinal tract fibers were also observed. Descending projections from brain stem catecholaminergic neuronal groups do not pass through the test sites of the dorsolateral funiculus, nor, apparently, do they go to make up the spinal locomotor strip. Specificity of the brain stem and spinal locomotor region is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 21, No. 3, pp. 327–335, May–June, 1989.     

Shining light into the black box of spinal locomotor networks

Rhythmic activity is responsible for numerous essential motor functions including locomotion, breathing and chewing. In the case of locomotion, it has been realized for some time that the spinal cord contains sufficient circuitry to produce a sophisticated stepping pattern. However, the central pattern generator for locomotion in mammals has remained a ‘black box’ where inputs to the network were manipulated and the outputs interpreted. Over the last decade, new genetic approaches and techniques have been developed that provide ways to identify and manipulate the activity of classes of interneurons. The use of these techniques will be critically discussed and related to current models of network function.     

Evolutionary divergence in developmental strategies and neuromodulatory control systems of two amphibian locomotor networks

Attempts to understand the neural mechanisms which produce behaviourmust consider both prevailing sensory cues and the central cellularand synaptic changes they direct. At each level, neuromodulationcan additionally shape the final output. We have investigatedneuromodulation in the developing spinal motor networks in hatchlingtadpoles of two closely related amphibians, Xenopus laevis andRana temporaria to examine the subtle differences in their behavioursthat could be attributed to their evolutionary divergence. At the point of hatching, both species can swim in responseto a mechanosensory stimulus, however Rana embryos often displaya more forceful, non-locomotory coiling behaviour. Whilst thesynaptic drive that underlies these behaviours appears similar,subtle inter-specific differences in neuronal properties shapemotor outputs in different ways. For example, Rana neurons expressN-methyl-D-aspartate (NMDA)/serotonin (5-HT)-dependent oscillations,not present in hatchling Xenopus and many also exhibit a prominentslow spike after-hyperpolarisation. Such properties may endowthe spinal circuitry of Rana with the ability to produce a moreflexible range of outputs. Finally, we compare the roles of the neuromodulators 5-HT, noradrenaline(NA) and nitric oxide (NO) in shaping motor outputs. 5-HT increasesburst durations during swimming in both Xenopus and Rana, but5-HT dramatically slows the cycle period in Rana with littleeffect in Xenopus. Three distinct, but presumably homologousNO-containing brainstem clusters of neurons have been described,yet the effects of NO differ between species. In Xenopus, NOslows and shortens swimming in a manner similar to NA, yet inRana NO and NA elicit the non-rhythmic coiling pattern.     

Development and functional organization of spinal locomotor circuits

The coordination and timing of muscle activities during rhythmic movements, like walking and swimming, are generated by intrinsic spinal motor circuits. Such locomotor networks are operational early in development and are found in all vertebrates. This review outlines and compares recent advances that have revealed the developmental and functional organization of these fundamental spinal motor networks in limbed and non-limbed animals. The comparison will highlight common principles and divergence in the organization of the spinal locomotor network structure in these different species as well as point to unresolved issues regarding the assembly and functioning of these networks.     

Development and neuromodulation of spinal locomotor networks in the metamorphosing frog

Metamorphosis in the anuran frog, Xenopus laevis, involves profound structural and functional transformations in most of the organism's physiological systems as it encounters a complete alteration in body plan, habitat, mode of respiration and diet. The metamorphic process also involves a transition in locomotory strategy from axial-based undulatory swimming using alternating contractions of left and right trunk muscles, to bilaterally-synchronous kicking of the newly developed hindlimbs in the young adult. At critical stages during this behavioural switch, functional larval and adult locomotor systems co-exist in the same animal, implying a progressive and dynamic reconfiguration of underlying spinal circuitry and neuronal properties as limbs are added and the tail regresses. To elucidate the neurobiological basis of this developmental process, we use electrophysiological, pharmacological and neuroanatomical approaches to study isolated in vitro brain stem/spinal cord preparations at different metamorphic stages. Our data show that the emergence of secondary limb motor circuitry, as it supersedes the primary larval network, spans a developmental period when limb circuitry is present but not functional, functional but co-opted into the axial network, functionally separable from the axial network, and ultimately alone after axial circuitry disappears with tail resorption. Furthermore, recent experiments on spontaneously active in vitro preparations from intermediate metamorphic stage animals have revealed that the biogenic amines serotonin (5-HT) and noradrenaline (NA) exert short-term adaptive control over circuit activity and inter-network coordination: whereas bath-applied 5-HT couples axial and appendicular rhythms into a single unified pattern, NA has an opposite decoupling effect. Moreover, the progressive and region-specific appearance of spinal cord neurons that contain another neuromodulator, nitric oxide (NO), suggests it plays a role in the maturation of limb locomotor circuitry. In summary, during Xenopus metamorphosis the network responsible for limb movements is progressively segregated from an axial precursor, and supra- and intra-spinal modulatory inputs are likely to play crucial roles in both its functional flexibility and maturation.     

Neuromodulation via conditional release of endocannabinoids in the spinal locomotor network

Endocannabinoids act as retrograde signals to modulate synaptic transmission. Little is known, however, about their significance in integrated network activity underlying motor behavior. We have examined the physiological effects of endocannabinoids in a neuronal network underlying locomotor behavior using the isolated lamprey spinal cord. Our results show that endocannabinoids are released during locomotor activity and participate in setting the baseline burst rate. They are released in response to mGluR1 activation and act as retrograde messengers. This conditional release of endocannabinoids can transform motoneurons and crossing interneurons into modulatory neurons by enabling them to regulate their inhibitory synaptic inputs and thus contribute to the modulation of the locomotor burst frequency. These results provide evidence that endocannabinoid retrograde signaling occurs within the locomotor network and contributes to motor pattern generation and regulation in the spinal cord.     

Statistical characteristics of unit activity in spinal locomotor centers

A statistical analysis of unit activity in spinal locomotor centers was undertaken on immobilized thalamic cats at rest and during generation of efferent discharges. Activation of the spinal locomotor generator was accompanied by shortening of interspike intervals in the spike sequences of neurons and a decrease in their fluctuations. Histograms of interspike intervals became more symmetrical under these circumstances and there was a considerable increase in the number of neurons whose activity showed regular fluctuations on autocorrelation histograms. Spike trains at rest were characterized by dependence of successive intervals, which increased during efferent discharge generation. The possible mechanisms of modification of the time structure of unit activity in spinal locomotor centers during their activation are discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 12, No. 2, pp. 192–198, March–April, 1980.     

Cross-correlation analysis of unit activity in spinal locomotor centers

Correlation analysis of unit activity in spinal locomotor centers was carried out in immobilized thalamic cats. Within a short time interval (the time shift of one spike train relative to the other during plotting of the cross-correlation histogram did not exceed 54 msec) correlation between the spike flows of these cells was absent, irrespective of the distance between them, both at rest and during efferent discharge generation. Spike flows of neurons could correlate only in the case of a long time interval (maximal time shift of one spike train relative to the other not less than 4–8 sec during plotting of the cross-correlation histogram). Weak correlation with a long time interval (4–8 sec) was found between changes in the momentary frequency of a neuron and the intensity of the discharge in the motor nerve, but no correlation was found between changes in momentary frequency of the neuron and intensity of discharge. The possible causes of the absence of correlation with a short time interval and its presence with a long time interval are discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 12, No. 3, pp. 283–289, May–June, 1980.     

Contribution of stretch reflexes to locomotor control: a modeling study

It is known that the springlike properties of muscles provide automatic load compensation during weight bearing. How crucial is sensory control of the motor output given these basic properties of the locomotor system? To address this question, a neuromuscular model was used to test two hypotheses. (1) Stretch reflexes are too weak and too delayed to contribute significantly to weight-bearing. (2) The important contributions of sensory input involve state-dependent processing. We constructed a two-legged planar locomotor model with 9 segments, driven by 12 musculotendon actuators with Hill-type force-velocity and monotonic force-length properties. Electromyographic (EMG) profiles of the simulated muscle groups during slow level walking served as actuator activation functions. Spindle Ia and tendon organ Ib sensory inputs were represented by transfer functions with a latency of 35 ms, contributing 30% to the net EMG profile and gated to be active only when the receptor-bearing muscles were contracting. Locomotor stability was assessed by parametric variations of actuator maximum forces during locomotion in open-loop ("deafferented") trials and in trials with feedback control based on either sensory-evoked stretch reflexes or finite-state rules. We arrived at the following conclusions. (1) In the absence of sensory control, the intrinsic stiffness of limb muscles driven by a stereotyped rhythmical pattern can produce surprisingly stable gait. (2) When the level of central activity is low, the contribution of stretch reflexes to load compensation can be crucial. However, when central activity provides adequate load compensation, the contribution of stretch reflexes is less significant. (3) Finite-state control can greatly extend the adaptive capability of the locomotor system.     

Responses of medullary and spinal cord neurons to simulataneous stimulation of two locomotor points

Responses of neurons in the medulla and cervical segments of the spinal cord to simultaneous repetitive stimulation (50 pps) of two locomotor points (LP) that exceed the threshold for evoking walking by one to two times were investigated in mesencephalic cats. In most cases a neuron responsed to stimulation of only one LP. Stimulation of a second LP usually enhanced the firing index of that response, if it was low. Or it decreased the firing index if it was high, and it had no effect if the firing index was about 0.1. Some of the neurons responded to stimulation of one LP by increasing the baseline activity, though the pulses were not locked to individual stimuli. The effect of stimulation of the second LP on this increase in activity depended on the size of the increase. Data were also obtained on the convergence of effects on single neurons from the ipsi- and contralateral LPs of the midbrain and medulla. Possible mechanisms of the summation of subthreshold excitation of a pair of LPs during the initiation of locomotion are discussed.Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow. Translated from Neirofiziologiya, Vol. 24, No. 4, pp. 471–481, July–August, 1992.     

Somatosensory paths proceeding to spinal cord and brain--centripetal and centrifugal control for human movement

The flow of fast-conducting somatosensory information proceeding from the human leg, and entering sensorimotor control processes, is modulated according to the demands of limb movement. Both centripetal (proceeding in from sensory receptor discharge) and centrifugal (proceeding out from motor control centres) convergences can cause modulation, as seen in human, dog, and cat studies. Spinal H-reflexes appear to be strongly centripetally modulated in magnitude, as do initial somatosensory-evoked potentials recorded from the scalp following transmission in fast-conducting afferents from the leg. From the brain and from locomotor pattern-generators, there is also centrifugal control onto fast-conducting somatosensory pathways from the leg, both serving spinal reflexes and ascending to the brain. One expression of the centrifugal control appears to be pattern-generator modulation of cutaneous reflexes. Centrifugal control also can be seen premovement, as spinal H-reflex facilitation. Further, it can be observed as reduction of reception at somatosensory cerebral cortex, when motor learning has occurred or when stimuli are less salient for the task. Fourteen research developments have been identified that involve the generalizability of effects, specific mechanisms, and somatosensory modulation in predictive control.