The anterolateral funiculus in the spinal cord in amyotrophic lateral sclerosis

We carried out a morphometric study on the myelinated fibers in the anterolateral funiculus (ALF) and lateral corticospinal tract (LCS) in the cervical segment of the spinal cord of 13 patients with classic amyotrophic lateral sclerosis (ALS), 6 of whom had been on a respirator: 5 age-matched subjects were used as controls. The results obtained revealed that: (1) the fiber-size distributions of the myelinated fibers in the ALF and LCS of the control subjects had peaks at 2 m; (2) there were marked and significant losses of large myelinated fibers in the ALF and LCS of ALS patients; (3) the patients who required respirator support showed more severe degeneration in the ALF than those who required none; and (4) the degree of myelinated fiber loss in the LCS did not correlate with either the illness duration or the history of respirator use.     

Spino-bulbar, spino-thalamic and medical lemniscal connections in the American opossum, Didelphis marsupialis virginiana

Projections from the spinal cord and dorsal column nuclei to more rostral levels of the neuraxis were investigated in seventeen adult opossums by the Nauta-Gygax and Fink-Heimer techniques. In all cases with spinal cord lesions a greater number of degenerating fibers distributed to the medulla and pons than to the midbrain and diencephalon. Numerous degenerating fibers ended within the medial reticular formation of the medulla and caudal pons, and within the lateral reticular formation of the rostral pons and midbrain. Degenerating fibers were numerous in the reticular formation following cervical and thoracic lesions, but sparse in specimens with damage restricted to either the lumbar or sacral spinal cord. The dorsal column nuclei received afferent connections from the well known dorsal funicular pathway and, although to a much lesser extent, from the main ventrolateral spinal bundle. Although most of the latter fibers ended in the subnucleus dorsalis and spinal vestibular nucleus, some penetrated into the gracile and cuneate nuclei. Conspicuous terminal degeneration was present within the inferior olivary nucleus following cervical and thoracic lesions, but was lacking in cases of either caudal lumbar or sacral cord lesions. The location of terminal degeneration within the lateral reticular nucleus is dependent upon the level of the lesion in the spinal cord. Degenerating fibers ended within the lateral vestibular nucleus in all cases of spinal cord hemisection, and within the medial portion of the facial nucleus in cases with a lesion rostral to C-4. After cervical and thoracic hemisections terminal fiber degeneration was present within the midbrain tegmentum, the periaqueductal gray, the intercollicular nucleus (Mehler,'69), the posterior thalamic nucleus, the ventrobasal nucleus, the parafascicular nuclei and the caudal nucleus ventralis lateralis. All thalamic nomenclature was taken from Oswaldo-Cruz and Rocha-Miranda, '68. In animals with more caudal lesions, no fiber degeneration was evident within the nucleus ventralis lateralis and so little within the ventrobasal nucleus that it was impossible to ascertain a somatotopic pattern of spinothalamic projections. Lesions of the dorsal column nuclei caused terminal degeneration within the inferior olivary nucleus, the pars lateralis of the nucleus of the inferior colliculus, the zona incerta, the posterior thalamic nucleus, the caudal part of the ventral lateral thalamic nucleus and the ventrobasal nucleus of the thalamus. Diffuse connections with the reticular formation, periaqueductal gray, midbrain tegmentum and the parafascicular complex were also observed. The results from small lesions indicate that the input to the ventrobasal nucleus in the opossum is organized in the typical mammalian fashion.     

Bulbospinal and intraspinal connections in normal and regenerated salamander spinal cord

The salamander is the only limbed adult vertebrate which can regenerate portions of cervical, thoracic, or lumbar spinal cord. While the salamander has been a popular model for regeneration of the spinal cord, it is still not known what portions of the nervous system participate in the regeneration process. In the experiments reported here we examine the bulbospinal and intraspinal projections to the lumbar spinal cord in normal and regenerated salamanders (Notophthalmus viridescens). HRP application to the lumbar enlargement of normal salamanders labeled cells in the ventral thalamus, the rostral tegmentum in the proposed homolog of the red nucleus, the reticular neurons of the rhombencephalon, and the midline regions of the rhombencephalon which are possibly equivalent to raphe nuclei of other vertebrates. In the brachial spinal cord HRP-labeled cells were located in dorsal, intermediate, and ventral regions of the spinal gray matter and tended to be located at the periphery of the gray matter. To examine the spinal circuitry of regenerated salamanders, animals received complete spinal transections at the junction of the thoracic and lumbar spinal cord, abolishing all spontaneous coordinated hindlimb and tail movements. Animals exhibited walking and swimming within 60 days at which time a pledget of HRP was inserted into a gap in the spinal cord made by a transection 10.0 mm (six animals) or 5.0 mm (one animal) caudal to the first lesion. On average, the number of HRP labeled brain stem neurons in regenerated animals was 40% of that found in normal animals. The number of labeled cells in the brachial spinal cord was within the range of normal animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

The onset and development of descending pathways to the spinal cord in the chick embryo

The ontogenetic development of afferent (supraspinal and propriospinal) as well as efferent (ascending) fiber connections of the spinal cord was examined following the injection of horseradish peroxidase (HRP) or wheat germ agglutinin HRP (WGA-HRP) into the cervical and lumbar spinal cords (or brains) of embryos ranging in age from 4 to 14 days of incubation. A few cells were first reliably retrogradely labelled in the pontine reticular formation on embryonic day (E) 4 and E5 following the injection of WGA-HRP into the cervical and lumbar spinal cord, respectively. Propriospinal projections to the lumbar spinal cord, originating from brachial spinal cord, were found by E5, and from the cervical spinal cord by E5.5. Ascending fibers arising from neurons in the lumbar spinal cord could be followed to rostral mesencephalic levels in E5 embryos. Thus, the earliest supraspinal, propriospinal, and ascending fiber connections appear to be formed almost simultaneously. Retrogradely labelled cells were found in the raphe, reticular, vestibular, interstitial, and hypothalamic nuclei in E5.5 embryos following lumbar injections of WGA-HRP. Except for neurons in cerebellar nuclei, all the cell groups of origin that project to the cervical spinal cord of posthatching chicks were also retrogradely labelled by E8. There was a delay in the time of appearance of the projections from various regions of the brain stem to the lumbar versus the cervical spinal cord, ranging from 0.5 to 7 days, but typically of about 3 days duration. A large number of cells located in the ventral hypothalamic region, just dorsal to the optic chiasma, were found to be labelled following cervical HRP injection between E6 and E10. These cells may represent transient projections that are present only during embryonic stages since no labelled cells were found in this region in the newly-hatched chick.     

Age-related changes of the myelinated fibers in the human corticospinal tract: a quantitative analysis

A quantitative analysis was made of the myelinated fibers in the lateral corticospinal tract (LCST) at the levels of the 6th cervical, 7th thoracic and 4th lumbar spinal segments in 20 patients between 19 and 90 years old, and who died of non-neurological diseases. The diameter frequency histograms of myelinated fibers of LCST showed a bimodal pattern with a sharp peak of the small myelinated fibers and broad slope of the large myelinated fibers. The ratio of small fiber to large fiber densities was significantly higher in the 6th cervical (P<0.05) and 4th lumbar segments (P<0.01) than in the 7th thoracic segments. The density of small myelinated fibers was significantly lowered with advancing age (P<0.050.001), while that of large myelinated fibers was not significantly decreased in the aged patients, although it showed a slight age-dependent declining tendency. Age-dependent decline of small fiber density was more prominent in the cervical and lumbar segments. Retraction of the axon-collaterals from large-diameter myelinated fibers, which are abundant in the cervical and lumbar segments, may contribute to the age-related diminution of the small myelinated fibers in the LCST.Part of this work was supported by grants from the Ministry of Welfare and Health of Japan, and a grant from Uehara Memorial Research Foundation     

Axonal degeneration and regeneration in sensory roots in a genital herpes model

Summary In a mouse model of genital herpes simplex virus type 2 (HSV-2) infection, roots of the lower spinal cord were examined 5 days to 6 months after inoculation. Using immunoperoxidase methods on paraffin sections, viral antigen was found in sensory ganglia, their proximal roots and distal nerves on days 5 and 6 after infection. In Epon sections, most mice had focal sensory root abnormalities in lower thoracic, lumbar or sacral levels. At days 7 and 10, lesions showed chiefly nerve fiber degeneration, particularly of large myelinated fibers. At 2 weeks, lesions contained relatively large bundles of small unmyelinated fibers with immature axon-Schwann cell relationships. From 3 to 6 weeks, lesions again contained many more small unmyelinated fibers than normal but, in increasing proportions, axons in bundles were isolated from their neighbors by Schwann cell cytoplasm, and Schwann cells having 11 relationships with axons showed mesaxon or thin myelin sheath formation. At later times, the proportion of small unmyelinated axons decreased in parallel with increased numbers of small myelinated axons. By 6 months, affected roots showed a relative reduction in large myelinated fibers, increased proportions of small myelinated fibers and Schwann cell nuclei. Numbers of unmyelinated fibers were reduced relative to 3- to 6-week lesions. Axonal degeneration and regeneration appears to be the chief pathological change in sensory roots in this model. If regenerated fibers arise from latently infected neurons, then establishment of latency is not a relatively silent event, but is associated with major long-lasting, morphologically detectable effects.     

Study of the neurons of the supraspinal systems of the cat brain using the method of retrograde axonal transport of horseradish peroxidase]

Horseradish peroxidase (HRP) was injected into cervical, thoracic, lumbar and sacral segments of 18 cats. In all the cases HRP was transported retrogradely to the brain stem neurons in the medial reticular formation, vestibular complex and the red nucleus. The present findings demonstrate that, in addition to the above mentioned groups, there exist several other groups of neurons. Many labelled neurons are present in the locus coeruleus and the nucleus subcoeruleus, ipsilaterally. These neurons seem to be located in the same position as the monoaminergic (catecholamine-containing) neurons. Labelled HPR-positive neurons are present in the retroambiguous nucleus and in the upper pontine tegmentum adjoining the rubrospinal tract, mainly contralaterally, in the bulbar raphe, the mesencephalic central gray and the hypothalamus, mainly ipsilaterally. The occurrence of retrograde-labelled neurons in the locus coeruleus and the dorsal hypothalamus after HRP injections as far caudally as the lumbar segments, indicates that these cell groups give rise to descending fibres which pass almost the entire length of the spinal cord.     

A study of fiber systems within the spinal cord of the domestic pig that subserve pain

A total of 21 domestic pigs were used in a study of spinal cord fiber systems which subserve a pain response in the pig. Distribution of fiber systems were determined by the placement of various lesions into the spinal cord and examining the animal for its ability to give a complete pain response. The Swank-Davenport modification of the Marchi technique for staining degenerating myelnated fibers was used to determine the pattern of trajectory of myelinated fibers along the spinal cord. Lesions were made at the cervical level in three animals and resulting pattern of degenerating fibers was compared with those of the other animals in which the lesions had been placed at lower thoracic levels. In most animals the lesions were limited to a single site on the spinal cord, but in six animals staggered, bilateral hemisections were made to determine whether or not these fiber systems are as diffuse in the pig as has been reported for the cat. The spinal cord fiber systems which subserve a pain response in the pig are located generally within the ventrolateral quadrant of the spinal cord. It was found that only a small portion of one lateral funiculus just ventral to the dorsal and ventral spinocerebellar tracts, if left intact, was sufficient for the elicitation of a pain response from either rear limb. The results presented here indicate that the fiber systems in the spinal cord of the pig which subserve pain responses are more diffuse than in carnivora or in primates.     

Morphometric evaluation of primary sensory neurons in experimental p-bromophenylacetylurea intoxication

Summary To evaluate the three-dimensional pathology of lumbar primary sensory neurons in p-bromophenylacetylurea intoxication, the number and size distribution of neurons and of myelinated fibers were evaluated at the L-6 spinal ganglion level and at proximal and distal levels of sural nerve and thoracic (proximal) and cervical (distal) levels of Goll's tract, respectively, 2 and 6 weeks after the intoxication in rats. The number and size distribution of ganglion neuron cell bodies were not significantly different between intoxicated and control rats. The distal level of sural nerve had, significantly fewer large myelinated fibers than did control, and a significantly higher frequency of fibers undergoing degeneration. Proximal levels of sural nerve showed similar, but less severe changes. Similarly, the myelinated fibers of Goll's tract were significantly more affected at cervical than at thoracic level. Therefore, by morphometric criteria both centrally and peripherally directed myelinated fibers are most affected distally and less affected proximally while neuron cell bodies are not affected at all. These three-imensional morphological changes must be taken into consideration in formulating possible mechanisms for the development of this neuropathy.     

Immunocytochemical localization of pro-opiomelanocortin-derived peptides in the adult rat spinal cord

A dispersed descending pro-opiomelanocortin (POMC) fiber system has been demonstrated by peroxidase-antiperoxidase (PAP) immunocytochemistry in the adult rat spinal cord. beta-endorphin, adrenocorticotrophic hormone (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH) and 16K immunoreactive fibers exist in the spinal cord from cervical down to sacral level. Descending fibers running parallel in the dorsolateral and lateral funiculus send collaterals ventromedially or medially to terminate in the gray matter surrounding the central canal, where nociceptive neurons have recently been located, in addition to those nociceptive cells in the dorsal horn. After spinal transection at lower thoracic level, POMC peptide immunoreactivities disappeared below the lesion. Moreover, no POMC cell bodies were found in the spinal cord. Therefore, the descending fibers are most likely of supraspinal origin.     

Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the motor system in adults that occurs in sporadic, familial, and Western Pacific forms. Involvement of non-motor pathways has been increasingly recognized, both clinically and pathologically. Although the usual course is relentlessly progressive with death in half the cases within three years from onset, it can sometimes be protracted. Degeneration and loss of large motor neurons in the cerebral cortex, brainstem, and cervical and lumbar spinal cord are characteristic. Marked reduction in the number of large myelinated fibers is notable in the cervical and lumbar ventral roots. Peripheral nerves show reduced numbers of large myelinated fibers, acute axonal degeneration at all levels, and distal axonal atrophy. Motor end-plates reveal small or absent nerve terminals. Subclinical non-motor system involvement includes neuronal loss in Clarke's nucleus and dorsal root ganglia, degeneration of non-motor tracts in the spinal cord, loss of receptors in the dorsal horns of the spinal cord, and myelinated fiber loss with segmental demyelination in sensory and mixed nerves. The serious implications of the diagnosis of ALS make it mandatory to exclude similar potentially treatable disorders. Management should be multidisciplinary, and discussions with the patient and family members should be frank and frequent. Discussions about ventilatory support should take place early in the disease so that death from respiratory failure can be prevented, when that is desired, and conversely to obviate the discontent and anger that accompany involuntary life on a ventilator.     

Parabrachial nucleus neurons projecting to the lower brain stem and the spinal cord. A study in the cat by the Fink-Heimer and the horseradish peroxidase methods

Direct projections from the parabrachial nucleus (PBN) to the lower brain stem and the spinal cord were examined in the cat by the Fink-Heimer and the horseradish peroxidase (HRP) methods. After placing lesions in the PBN, many fine degenerated fibers were seen contralaterally in the ventromedial portions of the caudal pontine reticular formation, and ipsilaterally in the lateral portions of the facial nucleus, the regions around the hypoglossal nucleus, and the regions around the ambiguus nucleus; some degenerated fibers were traced ipsilaterally down to the spinal cord. Subsequently, HRP injections were attempted into these regions where many fine degenerated fibers were observed. In cats injected with HRP into the lateral portions of the facial nucleus, the regions around the hypoglossal nucleus, the regions around the ambiguus nucleus, or the first cervical cord segment, many HRP-labeled neurons were seen in the ventral portions of the PBN. The mean of the average soma diameters of the PBN neurons labeled with HRP injected into the regions around the hypoglossal nucleus or the first cervical cord segment was significantly larger than that of the PBN neurons labeled with HRP injected into the lateral portions of the facial nucleus or the regions around the ambiguus nucleus.     

Internodal Schwann cell fingers in the ventral spinal roots in mice: incidence and relationship to the diameter of myelinated fibers

Internodal Schwann cell fingers were present in the lumbar, cervical, and thoracic spinal roots of adult mice at the age of 3 months, but they were not recognized in five mice examined at the age of 3 weeks. In the L4 ventral roots of ICR mice aged 3 months, the incidence of internodal Schwann cell fingers was 0.79% at the central-peripheral transitional zone and 2.43% at the distal regions, respectively. The ratio of axon diameter to total fiber diameter of myelinated fibers with internodal Schwann cell fingers was lower than that of fibers without them. Therefore, we conclude that internodal Schwann cell fingers are probably related to the developmental increase in the thickness of the myelin sheaths in the ventral spinal roots at all levels of the spinal cord.     

Spinal cord projections from the medial cerebellar nucleus in tree shrew (Tupaia glis)

Electrolytic lesions were placed in the medial cerebellar nucleus in tree shrews (Tupaia glis) or in fibers issuing from this nucleus. Brains and spinal cords were processed according to Fink-Heimer procedure following survival times of 2-7 days. In control animals lesions were placed in the cerebellar cortex and, in one case, in the olfactory bulb. Degenerating fibers were seen entering the cervical spinal cord and continuing to thoracic and lumbar levels. The projection is relatively profuse in the cervical cord, becoming sparse as the fibers proceed to more caudal levels. Fibers run in the lateral funiculus, predominantly contralateral to the lesion. Some fibers are observed to travel directly through the intermediate gray matter of the spinal cord. Preterminal degeneration is seen primarily in the intermediate gray of the spinal cord. Results are discussed in relation to typical locomotor behavior of tree shrew.     

Distribution of neurons in the lateral pontine tegmentum projecting to thoracic, lumbar and sacral spinal segments in the cat

The course of descending fibers projecting to the spinal cord and the arrangement of their parent cells located in various nuclei of the dorso-lateral pontine tegmentum were studied using the horseradish peroxidase (HRP) retrograde axonal transport technique. Retrogradely labeled neurons were found in the locus coeruleus (LC), subcoeruleus (SC), K?lliker-Fuse nucleus (KF) and in the lateral parabrachial nucleus (LPB) after HRP injections into various spinal segments. Neurons innervating the thoracic spinal cord were found to be arranged in the ventral portion of the LC and in the entire SC; their axons descended ipsilaterally. Neurons with descending axons to lumbar segments were seen mainly in the ventral portion of the LC and in the medial portion of SC. Most of their axons were also seen to descend ipsilaterally. Neurons projecting to sacral segments occurred in the entire LC and in the medial portion of the SC. Large part of descending fibers crossed the midline at the level of (or near) the termination site. Neurons of all portions of the KF and LPB projected to the thoracic spinal cord only ipsilaterally, while many descending fibers innervating the sacral segments crossed the midline.     

Differential effects of chronic partial myelotomies on monoamine levels in cat spinal cord

The concentrations of 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) were measured in samples of lumbar and cervical spinal cords from 6 cats with chronic (over 2 months) lesions of the thoracic spinal cord and from 7 unoperated cats. Lesions confined to the dorsal thoracic spinal cord significantly lowered lumbar concentrations of NE, but not 5-HT, compared with control lumbar or matched paired cervical samples. Both NE and 5-HT were significantly reduced by dorsal or ventral lesions that involved tissue ventral to the central canal. Only the largest lesion could be shown to reduce lumbar DA concentration.     

Axonal damage revealed by accumulation of beta-amyloid precursor protein in HTLV-I-associated myelopathy

We investigated the localization and extent of beta-amyloid precursor protein (APP) immunoreactivity as a sensitive marker for impairment of fast axonal transport in the spinal cords of patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The results from this study show that APP, used as a marker of early axonal damage in HAM/TSP lesions, is more intensively expressed in areas of active-inflammatory lesions than those of inactive-chronic lesions. The close localization to the areas containing inflammation (activation of macrophage/microglia) is striking and suggests that axonal damage is closely associated with inflammation in active-chronic lesions. Although inflammatory cell infiltration in the central nervous system (CNS) is rarely found in inactive-chronic lesions, a few clusters of APP+ axons are found in the spinal cord white matter in some cases. The presence of APP+ axons without relation to inflammatory cells in inactive-chronic lesions, suggest that soluble neurotoxic factors might induce axonal changes in the CNS of HAM/TSP. The occasional myelinated fibers in the anterior and posterior spinal roots in lower thoracic to lumbar levels had APP+ axons, suggesting that spinal nerve roots can be affected in HAM/TSP, especially in lower thoracic to lumbar levels. Impairment of fast axonal transport may contribute to the development of disability in patients with HAM/TSP.     

Funicular course of catecholamine fibers innervating the lumbar spinal cord of the cat

The purpose of this study was to determine the funicular location of descending catecholamine (CA) fibers innervating the lumbar spinal cord from the dorsolateral pons (DLP). The locations of catecholamine-containing cell bodies which project to the lumbar spinal cord were determined by combining the use of the retrogradely transported fluorescent dye, Evans Blue (EB), with the glyoxylic acid histofluorescence technique. Lumbar injections of Evans Blue were combined with thoracic lesions of the dorsolateral funiculi (DLF) or ventrolateral funiculi (VLF) in order to retrogradely label those CA-containing or non-CA-containing cell bodies whose axons descend within the spared hemispinal cord. By this technique it was determined that descending CA fibers innervating the lumbar spinal cord of the cat project through both the DLF and the VLF. The nucleus subcoeruleus, the Kolliker-Fuse nucleus and the CA cell bodies in the area of A5 each contain a significant number of CA-containing cells whose fibers descend both within the DLF and the VLF, while the nucleus locus coeruleus projects to the lumbar cord primarily through the VLF. Catecholamine cells of the DLP innervate the lumbar spinal cord bilaterally, although there is an ipsilateral predominance. The CA-containing cells of the DLP which innervate the contralateral spinal cord were shown by ipsilateral or contralateral thoracic hemisection to decussate both above and below the thoracic lesion. Non-CA-containing cells from the DLP also crossed at all levels of the spinal cord; however, cells from the caudal pons had a larger number of cells which crossed above the thoracic lesion while cells of the more rostral pons had a larger number of cells which crossed below the lesion.     

The rubro-spinal tract of the opposum (Didelphis virginiana)

The course, caudal extent and termination of the opossum rubro-spinal tract were determined by employing the Nauta-Gygax and Fink-Heimer techniques on the spinal cords of animals with lesions either within the red nucleus or within the descending fibers emanating from that nucleus. Prior to placement of the lesion, the area at the tip of the electrode was stimulated and the concomitant movements of skeletal muscles were palpated. The rubro-spinal tract traversed the entire length of the spinal cord and was located within the dorsolateral portion of the lateral funiculus. The tract was partially separated from the surface throughout cervical and thoracic levels by fibers of the dorsal spino-cerebellar tract. More caudally the rubro-spinal tract coursed immediately beneath the cord surface. At cervical levels, rubro-spinal fibers ended extensively within the lateral portion of laminae V and VI (Rexed, '52) and minimally within the medial portions of the same laminae. Fascicles also ended within lamina VII. At thoracic levels, lamina VI disappeared and rubro-spinal fibers terminated within the lateral and, to a lesser extent, the medial portions of laminae V and VII. Lamina VI was present at lumbar and rostral sacral levels and the majority of rubro-spinal fibers ended within the lateral part of that lamina. However, a few fibers terminated within laminae V and VII at such levels. At caudal sacral and coccygeal levels lamina VI disappeared and rubro-spinal bundles ended within laminae V and VII. Stimulation of the caudal red nucleus initiated contraction of the flexor musculature of the contralateral forelimb, and to a lesser degree, the contralateral hindlimb. Contraction of the contralateral paraxial musculature was also noted at cervical and thoracic levels during such experiments. Stimulation of the rubro-spinal tract and adjacent tegmentum immediately caudal to the red nucleus resulted in similar movements, but they were essentially limited to the side of the stimulation.