Influence of Vibration on Motor Responses in the Upper Arm Muscles under Stationary Conditions and during Voluntary and Evoked Arm Movements under Limb Unloading Conditions

Locomotion of mammals, including humans, is based on the rhythmic activity of spinal cord circuitries. The functioning of these circuitries depends on multimodal afferent information and on supraspinal influences from the motor cortex. Using the method of transcranial magnetic stimulation (TMS) of arm muscle areas in the motor cortex, we studied the motor evoked potentials (MEP) in the upper arm muscles in stationary conditions and during voluntary and vibration-evoked arm movements. The study included 13 healthy subjects under arm and leg unloading conditions. In the first series of experiments, with motionless limbs, the effect of vibration of left upper arm muscles on motor responses in these muscles was evaluated. In the second series of experiments, MEP were compared in the same muscles during voluntary and rhythmic movements generated by left arm m. triceps brachii vibration (the right arm was stationary). Motionless left arm vibration led to an increase in MEP values in both vibrated muscle and in most of the non-vibrated muscles. For most target muscles, MEP was greater with voluntary arm movements than with vibration-evoked movements. At the same time, a similar MEP modulation in the cycle of arm movements was observed in the same upper arm muscles during both types of arm movements. TMS of the motor cortex significantly potentiated arm movements generated by vibration, but its effect on voluntary movements was weaker. These results indicate significant differences in the degree of motor cortex involvement in voluntary and evoked arm movements. We suppose that evoked arm movements are largely due to spinal rather than central mechanisms of generation of rhythmic movements.     

Inhibition of murine retrovirus-induced neurodegeneration in the spinal cord by explant culture.

The neurovirulent chimeric mouse ecotropic retrovirus FrCasE causes a rapid neurodegenerative disease of the central nervous system (CNS) characterized by the appearance of spongiform lesions in motor areas 10 days after neonatal inoculation. To study the details of the pathogenic process, we examined the ability of an ex vivo spinal cord model to recapitulate disease. Organotypic spinal cord slice cultures were established from IRW mice 7 days after neonatal inoculation. This corresponds to a time when virus expression in the CNS is first detectable but spongiform changes have yet to evolve. Infectivity associated with these cultures peaked at 7 days in vitro and persisted at this level for 6 weeks. FrCasE infection of the spinal cord slices was primarily found associated with microglial cells. Infection of neurons, astrocytes, oligodendroglia, and endothelial cells was not observed; however, significant astrogliosis was found. Despite the presence of extensive microglial infection in close association with spinal motor neurons in organotypic cultures, no virus-specific spongiform degenerative changes were observed. These results suggest that removal of motor neurons from the developing CNS, despite maintaining the local cytoarchitectural relationships, prevents the virus from eliciting its pathological effects. Possible reasons for the interruption of lesion development are discussed.     

Ventral Horn Neuropeptides Modulate the Release of Noradrenaline from Tissue Slices of Rat Brainstem and Ventral Thoracic Spinal Cord

The release of endogenous noradrenaline (NA) from slices of adult rat brainstem and ventral thoracic spinal cord was investigated using a fixed-volume incubation technique and HPLC with electrochemical detection. Incubation with potassium (15-50 mM) produced a dose-related increase in basal NA release that was calcium dependent. The potassium-evoked release of NA from spinal cord or brainstem slices was potentiated according to dose by preincubation with either (a) the selective alpha 2-adrenoceptor antagonist idazoxan (10(-6)-10(-4) M) or (b) the thyrotrophin-releasing hormone (TRH) analogue RX 77368 (pGlu-His-3,3'-dimethyl ProNH2; 10(-5) and 10(-4) M). Incubation of spinal cord slices with the NA uptake inhibitor maprotiline (1 microM) enhanced the effect of idazoxan but inhibited that of RX 77368. The effects of RX 77368 and potassium alone (15 mM) on NA release from both spinal cord and brainstem slices were reduced to basal levels with tetrodotoxin (10(-7) M). Similarly, preincubation of spinal cord, but not brainstem, slices with the insect neuropeptide proctolin (10(-4) M) significantly attenuated the potassium- or RX 77368-induced release of NA, whereas substance P (3 X 10(-5) and 1 X 10(-4) M) had no effect on either tissue. These results suggest that changes in NA release in the spinal cord and brainstem may mediate some of the actions of neuropeptides in ventral spinal cord, although the peptides may not be acting directly on the noradrenergic nerve terminals in these tissues.     

Erectile function and bulbospongiosus EMG activity in estrogen-maintained castrated rats vary with behavioral context.

Electromyographic (EMG) activity in the bulbospongiosus muscles (BS) was recorded to monitor potential castration-induced alterations in muscle activity during copulation and reflexive erections. EMG recordings were made from intact male rats and from castrated rats maintained from 7 to 50 days on estradiol benzoate (300 micrograms/day) or testosterone (200 micrograms/day). Despite a 40-50% postcastration reduction in the weight of the BS and accessory sexual glands in estrogen-treated rats, the pattern of EMG activity during copulation was similar across groups. In estradiol-treated males, the EMG burst frequency during mounts and burst duration during intromissions exceeded the parameters of intact males and of castrated males maintained on testosterone. Between intromissions, and following ejaculatory patterns, estrogen-treated males displayed spontaneous muscle bursts accompanied by visually confirmed erection of the glans penis, but these males quickly lost the capacity for reflexive erections. These data demonstrate that despite castration-induced atrophy of the penile muscles and, presumably, their spinal motor nuclei, the motor output to these muscles is maintained following androgen removal. The capacity for substantial penile erection is retained during copulation long after reflexive erections have diminished.     

Sensorimotor regulation of movements: Novel strategies for the recovery of mobility

A series of observations have provided important insight into properties of the spinal as well as supraspinal circuitries that control posture and movement. We have demonstrated that spinal rats can regain full weight-bearing standing and stepping over a range of speeds and directions with the aid of electrically enabling motor control (eEmc), pharmacological modulation (fEmc), and training [1, 2]. Also, we have reported that voluntary control movements of individual joints and limbs can be regained after complete paralysis in humans [3, 4]. However, the ability to generate significant levels of voluntary weight-bearing stepping with or without epidural spinal cord stimulation remains limited. Herein we introduce a novel method of painless transcutaneous electrical enabling motor control (pcEmc) and sensory enabling motor control (sEmc) strategy to neuromodulate the physiological state of the spinal cord. We have found that a combination of a novel non-invasive transcutaneous spinal cord stimulation and sensory-motor stimulation of leg mechanoreceptors can modulate the spinal locomotor circuitry to state that enables voluntary rhythmic locomotor movements.     

CHANGES IN CENTRAL NORADRENALINE NEURONSADMINISTRATION AFTER SYSTEMIC 6-HYDROXYDOPAMINE ADMINISTRATION

—Intravenous injection of a large dose of 6-hydroxydopamine (100 mg/kg) to adult rats caused a significant and long-lasting reduction (about 30 per cent) of the in oirro uptake of [³H]NA in the cerebral cortex and spinal cord, while no changes were seen in the hypothalamus. The endogenous NA in whole brain was similarly reduced (about 20 per cent). Fluorescence histochemistry revealed catecholamine accumulations which are degenerative signs, induced by 6-hydroxydopamine, in axons of the dorsal NA bundle innervating the cerebral cortex. It is concluded that the blood–brain barrier in adult rats is not completely protective with respect to the neurotoxic action of systemically injected 6-hydroxydopamine, which can produce degeneration of a significant number of NA nerve terminals in the cerebral cortex and spinal cord. Previous studies have shown that 6-hydroxydopamine caused a permanent and selective degeneration of a large number of central NA nerve terminals when injected systemically up to 1 week after birth, due to an incompletely developed blood-brain barrier. This barrier for 6-hydroxydopamine develops between the 7th and 9th day after birth (Sachs , 1973). In the present study 6-hydroxydopamine was found to cause a small transient reduction in [³H]NA uptake in cerebral cortex of rats between 9 and 28 days of age, while in older rats the damage produced by 6-hydroxydopamine was long-lasting. Thus, the NA nerves ascending to the cerebral cortex seem to possess a regenerative capacity to a 6-hydroxydopamine-induced degeneration up to about 28 days postnatally, but which later disappears or is markedly retarded.     

Effects of morphine on the 6-hydroxydopamine induced changes of the postnatal development of central noradrenaline neurons

Neonatal treatment with the catecholamine neurotoxin 6-hydroxydopamine (6-OH-DA) leads to permanent noradrenaline (NA) denervations of distant projections (e.g. in the neocortex) with a concomitant NA hyperinnervation in regions close to the perikarya (e.g. in the cerebellum) a "pruning effect' mainly affecting the locus coeruleus NA neuron system. Morphine administration after 6-OH-DA produced a significant potentiation of the 6-OH-DA-induced NA depletion in the olfactory bulb, spinal cord, frontal and occipital cortex, with a tendency for NA to increase in the mesencephalon, pons-medulla and cerebellum, when analysed in the adult stage. Morphine treatment alone had no effects on the NA levels in any region studied. Morphine was found to counteract the NA depletion induced by tyrosine hydroxylase inhibition in neonate rats, indicating that morphine reduces NA turnover. The present results are compatible with the view that morphine potentiates the 6-OH-DA-induced degeneration of NA nerve terminals, possibly related to the inhibitory action on NA neurons.     

Selective depletion of spinal noradrenaline abolishes post-decapitation convulsions

Previous data have suggested that spinal noradrenaline (NA) might be important in the normal expression of post-decapitation convulsions. This hypothesis was tested by selective depletion of spinal NA through stereotaxic infusions of 6-hydroxydopamine into the medulla in adult rats. This treatment was found to substantially reduce spinal NA and to abolish the post-decapitation convulsions. The results are discussed in terms of the mechanism underlying the involvement of NA in this reflex.     

Comparison of electrical thresholds for evoking movements from sensori-motor areas of the cat cerebral cortex and its relation to motor training

Motor maps and electrical thresholds for evoking movements from motor areas of the cerebral cortex were evaluated in normal cats by using intracortical microstimulation techniques. Stainless steel chambers were implanted over craniotomies in adult cats trained to perform reaching and retrieval movements with their forelimbs. Prehensile motor training was continued and movement performance monitored for about 6–10 weeks during which the cortex was progressively explored with sharp tungsten electrodes inserted into cortical gyri (anterior and posterior sigmoid, and coronal) and the banks of sulci (cruciate, presylvian and coronal). Twice weekly, under light general anaesthesia, 3–4 tracks were made in either hemisphere till about 50 tracks were made in each hemisphere. Mean thresholds for evoking forelimb movements from different cytoarchitectonic areas (4γ, 4δ, 6aγ and 3a) were compared and no consistent or significant differences were observed between the different areas. In the animals (4/6) which used either forelimb to perform the tasks, there were no consistent differences in the mean thresholds for evoking forelimb movements from the two hemispheres. However, in 2 animals, which used their right forelimbs predominantly or exclusively to perform all the tasks, mean thresholds for evoking forelimb movements was significantly higher in areas 4γ and 6aγ of the left hemisphere (compared to the right); no consistent differences in the mean thresholds for evoking hindlimb or facial movements were observed between the two hemispheres. These findings suggest that ICMS thresholds for evoking forelimb movements may be similar in different sensorimotor areas of the cat cerebral cortex, and these thresholds could be influenced by motor training.     

Changes in electrical thresholds for evoking movements from the cat cerebral cortex following lesions of the sensori-motor area

We evaluated motor maps in the cerebral cortex and motor performance in cats before and after lesions of the forelimb representation in the primary motor area. After the lesion there was a reduction in the use of the affected forelimb and loss of accuracy in prehension tasks using the forelimb; some recovery occurred during the mapping study. Electrode tracts and lesion sites were located in cytoarchitectonically identified cortical areas 4γ, 4δ, 6aα, 6aγ, 3a. The lesions were mainly in area 4γ. In the lesioned hemisphere there were many points around the lesion site (in areas 4γ and 3a) from which movements could not be evoked. In some areas distant from the lesion site (e.g. area 6aγ) the mean thresholds for evoking forelimb movements were significantly elevated. Mean thresholds for evoking hindlimb and facial movements were not different from before. In the contralateral hemisphere mean thresholds for evoking forelimb, but not hindlimb or facial movements, were significantly elevated in several sensorimotor areas (area 4γ, 6aγ and 3a). Mean thresholds for evoking forelimb movements appeared to progressively increase during the time of study. Minimal currents required to evoke forelimb movements from the cerebral cortex increase (possibly progressively) following a lesion of the forelimb representation in the primary motor area, affecting many interconnected motor areas in the hemispheres ipsilateral and contralateral to the lesioned site. This increase in thresholds may play a role in the changes in cortical control of the affected and contralateral limbs following brain lesions and explain the increased sense of effort required to produce movements.     

Changes in electrical thresholds for evoking movements from the cat cerebral cortex following lesions of the sensori-motor area

We evaluated motor maps in the cerebral cortex and motor performance in cats before and after lesions of the forelimb representation in the primary motor area. After the lesion there was a reduction in the use of the affected forelimb and loss of accuracy in prehension tasks using the forelimb; some recovery occurred during the mapping study. Electrode tracts and lesion sites were located in cytoarchitectonically identified cortical areas 4gamma, 4delta, 6aalpha, 6agamma, 3a. The lesions were mainly in area 4gamma. In the lesioned hemisphere there were many points around the lesion site (in areas 4gamma and 3a) from which movements could not be evoked. In some areas distant from the lesion site (e.g. area 6agamma) the mean thresholds for evoking forelimb movements were significantly elevated. Mean thresholds for evoking hindlimb and facial movements were not different from before. In the contralateral hemisphere mean thresholds for evoking forelimb, but not hindlimb or facial movements, were significantly elevated in several sensorimotor areas (area 4gamma, 6agamma and 3a). Mean thresholds for evoking forelimb movements appeared to progressively increase during the time of study. Minimal currents required to evoke forelimb movements from the cerebral cortex increase (possibly progressively) following a lesion of the forelimb representation in the primary motor area, affecting many interconnected motor areas in the hemispheres ipsilateral and contralateral to the lesioned site. This increase in thresholds may play a role in the changes in cortical control of the affected and contralateral limbs following brain lesions and explain the increased sense of effort required to produce movements.     

Comparison of electrical thresholds for evoking movements from sensori-motor areas of the cat cerebral cortex and its relation to motor training

Motor maps and electrical thresholds for evoking movements from motor areas of the cerebral cortex were evaluated in normal cats by using intracortical microstimulation techniques. Stainless steel chambers were implanted over craniotomies in adult cats trained to perform reaching and retrieval movements with their forelimbs. Prehensile motor training was continued and movement performance monitored for about 6-10 weeks during which the cortex was progressively explored with sharp tungsten electrodes inserted into cortical gyri (anterior and posterior sigmoid, and coronal) and the banks of sulci (cruciate, presylvian and coronal). Twice weekly, under light general anaesthesia, 3-4 tracks were made in either hemisphere till about 50 tracks were made in each hemisphere. Mean thresholds for evoking forelimb movements from different cytoarchitectonic areas (4gamma, 4delta, 6agamma and 3a) were compared and no consistent or significant differences were observed between the different areas. In the animals (4/6) which used either forelimb to perform the tasks, there were no consistent differences in the mean thresholds for evoking forelimb movements from the two hemispheres. However, in 2 animals, which used their right forelimbs predominantly or exclusively to perform all the tasks, mean thresholds for evoking forelimb movements was significantly higher in areas 4gamma and 6agamma of the left hemisphere (compared to the right); no consistent differences in the mean thresholds for evoking hindlimb or facial movements were observed between the two hemispheres. These findings suggest that ICMS thresholds for evoking forelimb movements may be similar in different sensorimotor areas of the cat cerebral cortex, and these thresholds could be influenced by motor training.     

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.     

Contribution of Noradrenergic Neurons to the Regulation of Dopaminergic (D1) Receptor Denervation Supersensitivity in Rat Prefrontal Cortex

3,4-Dihydroxyphenylethylamine (DA, dopamine) levels in the rat prefrontal cortex were selectively decreased by 52%, leaving noradrenaline (NA) levels unaffected, 4 weeks following restricted bilateral electrolytic lesions of the ventral mesencephalic tegmentum (VMT). These lesions also induced a significant increase in DA-sensitive, but not isoproterenol-sensitive, adenylate cyclase activity in tissue homogenates (+38%). We had shown previously that chemical (6-hydroxydopamine, 6-OHDA) lesions of the VMT destroy both ascending DA and NA fibers but do not alter the D1-receptor density in the prefrontal cortex. In this study, electrolytic lesions of the VMT were combined with bilateral injections of 6-OHDA made laterally in the pedunculus cerebellaris superior to assess the role of NA fibers in the development of D1-receptor supersensitivity. This combined treatment produces a large decrease of cortical NA levels (-95%), an increase in beta-adrenergic-sensitive adenylate cyclase activity (+110%), and a decrease in DA levels (-60%), but does not alter D1-receptor density in the prefrontal cortex. These results indicate that the development of D1-receptor supersensitivity in the prefrontal cortex following electrolytic lesion of the VMT depends on the presence of an intact NA innervation.     

Involvement of Dopamine Neurons in the Regulation of β-Adrenergic Receptor Sensitivity in Rat Prefrontal Cortex

The contribution of dopamine (DA) afferents to the regulation of beta-adrenergic receptor sensitivity (isoproterenol-stimulated adenylate cyclase activity) in the rat prefrontal cortex was investigated by comparing the effects of lesions affecting either both DA and noradrenaline (NA) or NA fibers alone. Bilateral 6-hydroxydopamine (6-OHDA) lesions made in the ventral tegmental area destroyed ascending DA and to a variable extent ascending NA fibers innervating the prefrontal cortex. Two opposite effects were observed depending on the extent of cortical NA denervation: (a) When NA denervation was complete (less than 4% of controls), a marked increase in the isoproterenol-sensitive adenylate cyclase activity (+78%) was found. The amplitude of this denervation supersensitivity was similar to that occurring following complete and selective destruction of NA innervation induced by bilateral 6-OHDA injections made into the pedunculus cerebellaris superior. (b) When 6-OHDA injections into the ventral tegmental area led to a partial destruction of cortical NA afferents (10-40% of control values), a hyposensitivity of the isoproterenol-induced adenylate cyclase activity (-30%) was observed. This effect contrasted with the moderate supersensitivity seen in rats with partial, but selective, destruction of NA innervation (pedunculus cerebellaris superior lesions). The hyposensitivity of beta-adrenergic receptors obtained in rats with partial lesions of cortical NA fibers, but devoid of cortical DA innervation, suggests that DA neurons may regulate, under certain conditions, the denervation supersensitivity of beta-adrenergic receptors.     

Involuntary movements of the lower extremity following dorsal root entry zone lesions in a man treated for phantom limb pain

A patient developed continuous patterned involuntary movements of abduction-adduction, flexion-extension of his right lower extremity following surgical placement of spinal dorsal root entry zone lesions for the treatment of phantom limb pain. The stereotype movements were monitored by video and electromyographic recording of quadriceps femoris and hamstring muscles. Administration of para-chlorophenylbutyric acid (baclofen) dramatically stopped the involuntary movements and electromyographic silence ensued. Voluntary muscle movements were preserved. The theoretical implications of this unique movement disorder and central patterning of motor activity within the spinal cord are discussed.     

Distributions of active spinal cord neurons during swimming and scratching motor patterns

The spinal cord can generate motor patterns underlying several kinds of limb movements. Many spinal interneurons are multifunctional, contributing to multiple limb movements, but others are specialized. It is unclear whether anatomical distributions of activated neurons differ for different limb movements. We examined distributions of activated neurons for locomotion and scratching using an activity-dependent dye. Adult turtles were stimulated to generate repeatedly forward swimming, rostral scratching, pocket scratching, or caudal scratching motor patterns, while sulforhodamine 101 was applied to the spinal cord. Sulforhodamine-labeled neurons were widely distributed rostrocaudally, dorsoventrally, and mediolaterally after each motor pattern, concentrated bilaterally in the deep dorsal horn, the lateral intermediate zone, and the dorsal to middle ventral horn. Labeled neurons were common in all hindlimb enlargement segments and the pre-enlargement segment following swimming and scratching, but a significantly higher percentage were in the rostral segments following swimming than rostral scratching. These findings suggest that largely the same spinal regions are activated during swimming and scratching, but there are some differences that may indicate locations of behaviorally specialized neurons. Finally, the substantial inter-animal variability following a single kind of motor pattern may indicate that essentially the same motor output is generated by anatomically variable networks.     

Biochemical studies on monoamine contents in spinal cord of patients with multiple system atrophy

Monoamine contents were measured in the cervical spinal cord of patients with multiple system atrophy (MSA) by high-performance liquid chromatography with electrochemical detection. The concentrations of noradrenaline (NA) and its metabolite 4-methyl-4-hydroxyphenylglycol (MHPG) were highest in ventral horn compared with other regions of the spinal cord in controls. Both NA and MHPG contents were reduced in all regions in 4 MSA patients. But in one case (case 5), which did not show an autonomic dysfunction, NA as well as MHPG level was similar to controls. Similarly, the concentrations of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were highest in ventral horn and reduced in all regions in 4 MSA patients who showed mild motor weakness. In one case (case 5), which revealed clinical motor weakness associated with fasciculation and areflexia and pathological degeneration of ventral horn, 5-HT content showed higher values than controls whereas the 5-HIAA level was lower than controls. These results probably indicate that the cell loss of supraspinal monoaminergic nuclei may be one of the causes responsible for neurological dysfunction such as autonomic failures and motor weakness in MSA.     

Neural excitability of lower extremity musculature in individuals with and without chronic ankle instability: A systematic review and meta-analysis

This systematic review and meta-analysis examined differences in lower extremity neural excitability between ankles with and without chronic ankle instability (CAI). We searched the literature for studies that compared corticomotor or spinal reflexive excitability between a CAI group and controls or copers, or between limbs of a CAI group. Random effects meta-analyses calculated pooled effect sizes for each outcome. Nineteen studies were included. Meta-analyses of motor thresholds of the fibularis longus (Z = 1.17, P = 0.24) and soleus (Z = 0.47, P = 0.64) exhibited no differences between ankles with and without CAI. Pooled data indicate that ankles with CAI had reduced soleus spinal reflexive excitability (Z = 2.18, P = 0.03) and significantly less modulation of the soleus (Z = 6.96, P < 0.01) and fibularis longus (Z = 4.75, P < 0.01) spinal reflexive excitability when transitioning to more challenging stances. Pre-synaptic inhibition was facilitated in ankles with CAI (Z = 4.05, P < 0.01), but no difference in recurrent inhibition existed (Z = 1.50, P = 0.13). Soleus spinal reflexive activity is reduced in those with CAI. Reduced ability of ankles with CAI to modulate soleus and fibularis longus reflexive activity may contribute to impaired balance.     

Modular organization of finger movements by the human central nervous system

The motor system may generate automated movements, such as walking, by combining modular spinal motor synergies. However, it remains unknown whether a modular neuronal architecture is sufficient to generate the unique flexibility of human finger movements, which rely on cortical structures. Here we show that finger movements evoked by transcranial magnetic stimulation (TMS) of the primary motor cortex reproduced distinctive features of the spatial representation of voluntary movements as identified in previous neuroimaging studies, consistent with naturalistic activation of neuronal elements. Principal component analysis revealed that the dimensionality of TMS-evoked movements was low. Principal components extracted from TMS-induced finger movements resembled those derived from end-postures of voluntary movements performed to grasp imagined objects, and a small subset of them was sufficient to reconstruct these movements with remarkable fidelity. The motor system may coordinate even the most dexterous movements by using a modular architecture involving cortical components.