Postsynaptic potentials in motoneurons caused by spinal cord stimulation in humans

Epidural spinal cord stimulation (SCS) causes facilitation and/or inhibition of spinal motoneurons many segments below the level of the cathode. On the assumption that a spinal cord pathway is activated by the cathode the conduction velocity of the fiber system responsible for the facilitation of soleus motoneurons was estimated to be between 21.5 and 27 m/sec. It is clear that SCS in man can generate postsynaptic potentials in spinal neurons and thus is capable of modifying transmission in spinal segmental pathways.     

Corticospinal projections to upper and lower limb spinal motoneurons in man.

The pattern of muscle activation produced by magnetic stimulation over the human motor cortex has been examined in normal subjects. Magnetic stimulation elicited short latency compound muscle action potentials (CMAPs) from upper limb muscles contralateral to the stimulus and from lower limb muscles bilaterally. In the upper limb, the hand and forearm muscles had the lowest thresholds for activation and the largest CMAPs. There was little or no activation of the more proximal muscles, biceps and tricepts. In the lower limb the extensor digitorum brevis and tibialis anterior had low thresholds and large CMAPs. There was little or no short latency activation of soleus. This pattern of muscle activation remained the same even when the stimulating coil was moved to various locations within a radius of 3 cm from the vertex. Recordings from individual tibialis anterior and soleus motor units indicated that the differential activation of these muscles reflected the relative amplitudes of the short latency postsynaptic potentials produced by magnetic stimulation in their motoneurons. The 'jitter' in the activation of single muscle fibers by magnetic stimulation suggests that these projections are monosynaptic. It is argued that the pattern of muscle activation reflects the projections from the cortex to motoneurons rather than the projections of afferents onto cortical neurons. We conclude that magnetic stimulation can be used to identify the projections of the corticospinal pathways in man.     

Acute modulation of synaptic transmission to motoneurons by BDNF in the neonatal rat spinal cord

We investigated the acute effects of bath applied BDNF on synaptic input to motoneurons in the hemisected spinal cord of the neonatal rat. Motoneurons were recorded intracellularly, and BDNF-induced modulation of the synaptic response to stimulation of the homologous dorsal root (DR) and the ventrolateral funiculus (VLF) was examined. All motoneurons exhibited long-lasting (up to several hours) depression of the DR-activated monosynaptic AMPA/kainate-receptor mediated EPSP in response to BDNF but in about half of the motoneurons this was preceded by facilitation. VLF-evoked AMPA/kainate EPSPs in the same motoneurons were unaffected. BDNF effects were blocked by K252a and were not observed in neonates older than 1 week. Bath applied NMDA antagonists APV and MK-801 abolished both facilitatory and inhibitory actions of BDNF on the AMPA/kainate responses indicating the requirement for functional NMDA receptors. The pharmacologically isolated, DR-evoked, NMDA receptor-mediated response exhibited the same pattern of changes after BDNF superfusion. When introduced into the motoneuron through the recording microelectrode, MK-801 selectively blocked the facilitatory action of BDNF. Furthermore, BDNF enhanced NMDA-induced depolarization of the motoneuron in the presence of tetrodotoxin (TTX), thus, confirming its facilitatory effect on motoneuron NMDA receptors. Bath application of either BDNF or NMDA depressed the monosynaptic EPSP after selective blockade of postsynaptic NMDA receptors indicating a role for presynaptic NMDA receptors in BDNF-induced inhibitory action. Thus, BDNF-induced facilitation of monosynaptic EPSPs in neonatal rats is mediated by direct effects on postsynaptic NMDA receptors, while its inhibitory action occurs presynaptically.     

Properties of NMDA receptors in rat spinal cord motoneurons

Postnatal development and properties of N-methyl-d-aspartate (NMDA) receptors were studied with whole-cell and outside-out patch-clamp techniques in interneurons and fluorescence-labelled motoneurons in rat spinal cord slices. Both the absolute amplitude of NMDA-induced currents and currents normalized with respect to the motoneuron capacitance increased significantly at postnatal days 10-13 when compared to the responses evoked at postnatal days 2-3. The mean amplitude of the responses to kainate also increased in motoneurons of postnatal days 10-13. Single-channel currents induced by low concentrations of glutamate, exhibited four distinct amplitude levels corresponding to 19.2 +/- 2.4 pS, 38.4 +/- 3.5 pS, 56.3 +/- 2. 4 pS and 69.6 +/- 3.7 pS. In contrast, the conductance of single channels, recorded under identical conditions, in rat spinal cord interneurons was less, 15.3 +/- 3.2 pS, 29.9 +/- 5.4 pS, 46.7 +/- 4. 8 pS and 62.4 +/- 3.9 pS. The high (56/70 pS) conductance single-channel openings in motoneuron patches were sensitive to NMDA receptor inhibitors D-2-amino-5-phosphonovalerate, 7-chlorokynurenic acid and ifenprodil. Whole-cell NMDA-evoked currents were blocked in a voltage-dependent manner by extracellular Mg2+ with an apparent dissociation constant for Mg2+ binding at 0 mV of 1.8 +/- 0.5 mm. The conductance and relative distribution of NMDA receptor channel openings induced by 1 micrometer glutamate in patches isolated from the motoneurons were independent of age from postnatal day 4 to 14. The results suggest that the properties of NMDA receptor channels in motoneurons differ from those in spinal cord interneurons and cells transfected with NR1/NR2 subunits.     

Quantitative analysis of synaptic boutons on motoneurons of rhesus monkey spinal cord after chronic deafferentation due to cerebral lesions

The motoneurons in the lateral nucleus of the anterior horn of the rhesus monkey cervical enlargement were reconstructed by light microscopy of semi-thin sections of 2 micro in thickness which were cut serially, alternately with ultra-thin sections for electron microscopy. Four single neurons were reconstructed with a computer graphic system, and simultaneously the synaptic boutons on the soma and each dendrite of single reconstructed neurons were analyzed quantitatively by electron microscopy. The synaptic boutons were classified into 4 types on the basis of the shape of the synaptic vesicles. The F-type boutons with flattened vesicles, S-type with spherical vesicles, G-type with cored vesicles and large L-type boutons with smaller and polymorphic vesicles, were almost identical to the boutons categorized by Bodian (1966b). The F-type boutons represented the major type in terms of the covering ratio and synaptic population. The S-type boutons tended to occur more frequently on dendrites. The motoneurons of the same region were also investigated in a similar manner after chronic deafferentation by the ablation of the upper extremity area of the left cerebral cortex. F-type of boutons were significantly increased, especially on the dendrites, compared with the synaptic distribution of the normal motoneurons.     

Neonatal mammalian spinal cord neurons and motoneurons in monolayer culture

Previously, embryonic tissues have been used to produce monolayer cultures containing mammalian spinal cord neurons (SCN) and motoneurons (MN) for studies of the pathophysiology of motoneuron diseases. We demonstrate here that viable SCN and MN were observed in dissociated cultures from neonatal rat and mouse. These SCN and MN produced neurites and expressed acetylcholinesterase, neuron-specific enolase and neurofilament protein. These results indicate that cultured postnatal SCN and MN are capable of survival, neurite extension, and phenotypic expression in culture.     

Androgen regulates synaptic input to motoneurons of the adult rat spinal cord

Adult male rats (Sprague-Dawley) were castrated and implanted subcutaneously with Silastic capsules containing testosterone or nothing. Sham-castrated males served as controls. Four weeks following castration, cholera toxin-horseradish peroxidase (CT-HRP) was injected bilaterally into the bulbocavernosus muscles and animals were sacrificed 2 d later. The spinal cords containing the spinal nucleus of the bulbocavernosus (SNB) were dissected, processed with a modified tetramethylbenzidine (TMB) method for visualization of retrogradely transported CT-HRP, and examined at the ultrastructural level. Neuronal structures apposing the membranes of 150 TMB-labeled SNB neurons were analyzed by measuring the percentage of somatic and proximal dendritic membranes covered by synaptic contacts, synaptoid contacts, and neuron-neuron contacts. Most of the neuronal structures in the control and experimental SNB motoneurons consisted of synaptic contacts. The mean percentage of somatic and proximal dendritic membranes covered by synapses 4 weeks after castration was reduced to approximately 30% of those in control animals. However, treatment with testosterone for 4 weeks after castration prevented this decline. Castration and testosterone treatment also influenced the size and number of synaptic contacts per unit length of somatic and proximal dendritic membranes, and the incidence of neuron-neuron contacts and double synapses onto SNB motoneurons. These results indicate that androgen is critical for maintaining the organization of synaptic inputs to these spinal motoneurons in adult male rats.     

Serotonergic fiber sprouting to external anal sphincter motoneurons after spinal cord contusion

The present study analyzed the anatomical plasticity of serotonergic immunoreactive projections to external anal sphincter (EAS) motoneurons, and the behavioral plasticity of EAS reflexes, penile erection, and locomotion in rats with spinal contusion injury (SCI) or complete spinal cord transection (TX). Electromyographic activity of the EAS, penile erection latency, and BBB locomotor score exhibited parallel recovery over the 6-week recovery period after contusion SCI. This pattern of recovery was not observed in TX animals. While locomotor scores demonstrated a small increase after TX, erectile and anorectal function remained at abnormal levels established immediately after injury. Serotonergic immunofluorescent (5-HT-IF) staining at the lesion site identified a small number of fibers spared after SCI that may provide a substrate for functional recovery. Pixel density measurements of 5-HT-IF in the vicinity of retrogradely labeled EAS and unlabeled pudendal motoneurons necessary for penile erection provide indirect evidence of serotonergic sprouting that parallels the observed functional recovery in animals with SCI. No 5-HT-IF was detected caudal to the injury site in TX animals. These studies indicate: (1) lumbosacral eliminative and reproductive reflexes provide a valid means of studying the mechanisms of post-SCI plasticity; (2) the similar recovery curves suggest similar return of descending control, perhaps through sprouting of descending serotonergic fibers; (3) the observed deficits after TX likely represent the permanent removal of descending inhibition and reflect reorganization of segmental circuitry.     

Development and regulation of response properties in spinal cord motoneurons

The intrinsic response properties of spinal motoneurons determine how converging premotor neuronal input is translated into the final motor command transmitted to muscles. From the patchy data available it seems that these properties and their underlying currents are highly conserved in terrestrial vertebrates in terms of both phylogeny and ontogeny. Spinal motoneurons in adults are remarkably similar in many respects ranging from the resting membrane potential to pacemaker properties. Apart from the axolotls, spinal motoneurons from all species investigated have latent intrinsic response properties mediated by L-type Ca2+ channels. This mature phenotype is reached gradually during development through phases in which A-type potassium channels and T-type calcium channels are transiently expressed. The intrinsic response properties of mature spinal motoneurons are subject to short-term adjustments via metabotropic synaptic regulation of the properties of voltage-sensitive ion channels. Recent findings also suggest that regulation of channel expression may contribute to long-term changes in intrinsic response properties of motoneurons.     

Extensive proliferation of peripheral type myelin in necrotic spinal cord lesions of multiple sclerosis

Peripheral type "remyelination" in the spinal cord was investigated in a 34-year-old woman with relapsing multiple sclerosis (MS) over 7 years following her initial presentation with myelopathy. Confined to the large necrotizing cord lesions involving the gray matter, there was prominent proliferation of peripheral type myelin, measuring up to one-third of the cross-sectional field of the cord. These nerve bundles with peripheral type myelin, which was devoid of glial fibrillary acidic protein immunoreactivity, consisted of relatively monotonous, small-caliber nerve fibers arranged in parallel along the long axis of the cord. The ratio of the myelin thickness to axonal diameter was not as small as that of the ordinary remyelination. Co-existing abundant neuroma formation indicated exuberant regenerative activity of the peripheral nerves. These findings suggest that the peripheral nerve fibers with their axons originating from nerve roots may enter the necrotic MS cord lesions in such a way as to manifest in spinal cord trauma. Relatively frequent occurrence of this extensive proliferation of peripheral type myelin in Japanese MS subjects appears to be related to the severity of tissue destruction experienced in Japanese as compared with that of occidental MS.     

Experimental spinal cord compression by epidural neoplasm

We have developed an experimental model of spinal cord compression in rats. Tumor injected anterior to the T-12 vertebral body grows through the intervertebral foramina to compress the cord and produces paraplegia in 3 to 4 weeks. Evidence for vasogenic edema in spinal cord compressed by tumor includes increased water content, leakage of horseradish peroxidase into gray matter, and histologic evidence of edema. The vascular supply to the cord overlying the tumor appears to be compromised. Both spinal cord edema and clinical symptoms are lessened by treating symptomatic animals with dexamethasone.     

Modification of astrocytes in the spinal cord following dorsal root or peripheral nerve lesions

Glial fibrillary acidic protein (GFAP) immunocytochemistry was used to monitor the response of astrocytes in the rat spinal cord to either dorsal root or sciatic nerve lesions. Image analysis methods were used to provide a quantitative correlate of the reactive gliosis. Multiple dorsal root section elicited a rapid increase in GFAP immunoreactivity of astrocytes unilaterally within the spinal cord along the pathway of the degenerating dorsal root axons in the dorsal and ventral horns and this gliosis persisted in the dorsal horn beyond the time at which active phagocytosis of degenerative debris occurred. Labeling of proliferating cells using [3H]thymidine revealed that none of the dividing cells contained detectable GFAP, suggesting that the increased GFAP labeling represents primarily a hypertrophy rather than a proliferation of astrocytes. Comparison of animals that had been deafferented in the early neonatal period with those deafferented as adults indicated that the GFAP immunoreactive response persisted following neonatal lesions but that it was markedly less intense than after adult lesions. Sciatic nerve section in adults does not result in extensive frank degeneration but it does evoke a rapid and marked increase in staining of astrocytes both in the dorsal horn and in the ventral horn. Transganglionic changes in GFAP staining in the dorsal horn occur by 3 days post-operatively, which is much earlier than the time of dorsal root ganglion neuron death caused by the sciatic nerve lesion. These experiments indicate that astrocytes can respond to signals from a variety of changes in neurons, including not only Wallerian degeneration, but also retrograde and transganglionic changes.     

Rehabilitation after spinal cord injuries complicated by previous lesions

Since Sir Ludwig Guttmann introduced the comprehensive modern clinical approach to the rehabilitation of spinal cord injured patients much experience has been accumulated. Modern spinal cord injuries centres have opened throughout the world, treating mainly acute spinal cord injuries in young patients. At Stoke Mandeville Hospital we have had the opportunity to treat several spinal patients who had suffered previous neurological or orthopaedic disorders. These complicated combinations affected the rehabilitation process and the presentations show clearly different aspects of the problem.     

Epidemiology of spinal cord lesions in Denmark

Denmark has a population of about 5.2 million. The rehabilitation of spinal cord injured (SCI) takes place in two specialised rehabilitation hospitals. The incidence of new traumatic SCI admitted to these hospitals in the period 1975-1984 was 9.2 per million per year. During this period 92 Danes with non-traumatic and 268 with newly sustained traumatic spinal cord lesions were admitted to the rehabilitation hospital in Hornboek, which uptake area corresponded to South and East Denmark and Greenland and the Faroe Islands. Among the traumatic SCI 47% were due to traffic accidents, 23% to falls to a level below, 8% to attempted suicides, 6% to shallow water diving, and 6% to sporting accidents. The number of SCI caused by traffic accidents was found to decrease coincidently with the introduction of general speed limits and compulsory seat belt wearing. The male/female ratio was for the traumatic SCI 3.3, which was significantly lower than in the preceding 10-year period. 40% of all traumatic SCI were sustained at 15-24 years of age, and 51% had tetraplegia. Traffic accidents gave rise to more cervical, and falls to more caudal lesions. 41% of the traumatic SCI had an improvement in their neurological status after their admission to the neurosurgical department until the discharge from the rehabilitation hospital. Those with incomplete lesions showed greater improvement than those with complete lesions regardless of the level. Complete cervical lesions had significant better remissions than complete thoracic/lumbar lesions.     

Transsynaptic degeneration of motoneurones caudal to spinal cord lesions

We studied the effects of complete transversal section of the spinal cord, at T8-10, in adult rats, upon the number and morphology of identified motoneurones in lumbar segments L4 and L5. In observations by light and electron microscopy many lumbar motoneurones had structural abnormalities when the interval between surgery and perfusion ranged between a few hours and one week. We found also that as many as 25% of the motoneurones distal to a cord transection disappeared as a consequence of the lesions. We did not find comparable changes in the spinal cord at C6 after transection at T8-10. Complete removal of the cerebellum did not reduce the lumbar motoneurone counts. Bilateral ablation of the "motor" cortex did cause a reduction of motoneurone counts at L4-5; these animals showed normal or near normal spontaneous locomotor activity beginning a few days after the lesion was placed. Motoneurone counts were significantly reduced after partial cord lesions that spared the dorsal funiculi (where the corticospinal tract travels in the rat), but in this case the rats were paraplegic as a result of the lesion. Cord transection at 7 days of postnatal age resulted in reduced motoneurone counts when the rats reached adulthood. Intraspinal or subarachnoid administration of colchicine led to reduced motoneurone counts. Prolonged infusion of a GABA agonist, muscimol, into the lumbar CSF did not prevent the loss of motoneurones produced by cord transection. Pretreatment of animals with a Ca2+ channel blocker (nimodipine) did not prevent the effects of cord transection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Athetosis-dystonia in intramedullary lesions of spinal cord

Athetosis and dystonia are well known clinical signs, described in disorders of basal ganglia. As opposed to pseudoathetosis, true athetosis was hitherto not reported in cord lesions. We here report three patients with athetosis and dystonia of hands due to intramedullary lesions of cervical cord: two patients with syringomyelia and one with glioma. Even though pseudoathetosis can be produced by lesions of posterior columns and likely to be confused with the involuntary movements of our patients, they had clinical and EMG findings consistent with true athetosis. A possible explanation for the athetosis and dystonia due to cord lesion is being postulated.