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An autopsied case of Joseph disease with severe atrophy of the brain stem tegmentum is reported. A Japanese male noticed unsteady gait at age 30 and showed cerebellar ataxia, pyramidal signs, progressive external ophthalmoplegia, peripheral amyotrophy, sensory disturbance, and bradykinesia. He also developed mild dementia and nocturnal delirium at the terminal stage of his illness. His mother, older and younger brothers and daughter also presented progressive ataxia. The mode of inheritance is considered to be autosomal deminant. He died of cardiac failure at age 57. The autopsy revealed significant atrophy of the brain stem and spinal cord. Microscopic examination showed severe degeneration of the dentato-rubral and subthalamo-pallidal systems, pontine nuclei, spinal anterior horn, Clarke's column, accessory cuneate nucleus and spinocerebellar tract, moderate degeneration of the brain stem motor nuclei including the oculomotor nuclei and substantia nigra, and mild degeneration of the spinal posterior and intermediolateral column, and cerebellar cortex. An additional finding, which has received little attention in this disease, was severe atrophy of the brain stem tegmentum associated with degeneration of the reticular formation, raphe nuclei and locus ceruleus. The significance of brain stem tegmental atrophy in Joseph disease is discussed.

In four new-born Braunvieh calves suffering from connate recumbency and body tremor, a hitherto not described myelination disorder of the spinal cord was examined. Bilateral symmetric hypo- as well as demyelination in several spinal tracts were the most conspicuous findings, affecting the ascending gracile funiculus, the ascending dorsolateral spinocerebellar tract, and the mainly descending sulcomarginal tract. Deficient myelin production, loss of myelin, consecutive axonal degenerations, and prominent astrogliosis within these tracts were the histological hallmarks of the disease. This possibly inherited primary myelination disorder of the spinal cord differs markedly from known hereditary neurological diseases in Brown Swiss and Braunvieh cattle, respectively, i.e. the weaver-syndrome and the spinal muscular atrophy.

Strong evidence that premotor interneurons provide ventral spinocerebellar tract (VSCT) neurons with feedback information on their actions on motoneurons was previously found for Ia inhibitory interneurons and Renshaw cells, while indications for similar actions of other premotor interneurons were weaker and indirect. Therefore the aim of the present study was to reexamine this possibility with respect to interneurons relaying actions of group Ib afferents from tendon organs and group II afferents from muscle spindles. In all, 133 VSCT neurons in the L3–L5 segments (including 41 spinal border neurons) were recorded from intracellularly in deeply anesthetized cats to verify that stimuli applied in motor nuclei evoked monosynaptic inhibitory postsynaptic potentials (IPSPs) attributable to stimulation of axon collaterals of premotor interneurons. IPSPs were found in over two thirds of the investigated neurons. When intraspinal stimuli were preceded by stimuli applied to a muscle nerve at critical intervals, IPSPs evoked from motor nuclei were considerably reduced, indicating a collision of nerve volleys in axons of interneurons activated by group I and group II afferents. In individual VSCT neurons monosynaptic IPSPs were evoked from both biceps–semitendinosus and gastrocnemius–soleus motor nuclei, in parallel with disynaptic IPSPs from group Ib and group II as well as group Ia afferents. These observations indicate that individual VSCT neurons may monitor the degree of inhibition of both flexor and extensor motoneurons by premotor interneurons in inhibitory pathways from group Ib and group II afferents to motoneurons. They may thus be providing the cerebellum with feedback information on actions of these premotor interneurons on motoneurons.

Spinocerebellar (SC) neurons in the lumbosacral enlargement (LSE) give rise mainly to crossed fibers and generally terminate in parasagittal bands in the granular layer of the chicken cerebellar cortex. However, parasagittal bands for mossy fiber terminals have not always been clear in some cerebellar folia. The present study aimed at (1) observing the course in the spinal cord of the spinocerebellar tracts (SCTs), (2) confirming whether SC fibers originating from the unilateral LSE terminate in parasagittal bands, and (3) elucidating the relationship between the ventral and lateral funicular parts of the SCTs in the cervical enlargement (CE) using anterograde and retrograde labeling methods. The SCTs were located in the medial part of the ventral funiculi in spinal segment (SS) 27, the full width of the ventral funiculi in SS 22, the lateral and ventral funiculi in SS 14 and in the lateral funiculi from SS 10 rostralward. Projection areas in the cerebellar cortex of SC fibers were studied following unilateral injections of WGA-HRP into the LSE. As a result, SC fibers from the LSE terminated bilaterally in parasagittal bands of folia II–VI and IXc. Labeled terminals in the injected side were similar in number to those in the other side in folia II–IV and IXc and more than those in the other side in folia V and VI. Following ablation of the left (contralateral) lateral funiculus of the CE, the same tracer was injected into the right (ipsilateral) LSE or into the anterior or posterior cerebellar lobe. As a result, anterogradely labeled SC fibers passing through the ventral funiculus in the CE mainly terminated in the contralateral cerebellar cortex in folia II, III and IV, and in the ipsilateral cerebellar cortex in folia V, VI and IX. Following ablation of the unilateral lateral funiculus, retrogradely labeled neurons in the contralateral LSE were found in all SC neuron groups showing marked reduction in number. Thus, the ventral and lateral funicular parts of the SCTs in the CE were not pathways for specific SC neuron groups but different in projection areas.

Spinocerebellar ataxia type 6 is a late onset autosomal dominantly inherited ataxic disorder, and previous patho-anatomical studies have only reported neurodegeneration in SCA6 as being confined to the cerebellar cortex, dentate nucleus and inferior olive. However, the characteristics of cerebellar symptoms and many poorly understood "extracerebellar" symptoms reveal the three cerebellar regions and the corresponding precerebellar nuclei may undergo differing evolution of the degenerative process, and a more widespread brainstem degeneration in SCA6. We carried out a detailed immunohistochemical study in two SCA6 patients who had rather early onset and short disease duration with 25 CAG repeats, which is atypical for SCA-6. We investigated the severity of neurodegeneration in each of the cerebellar regions and the corresponding precerebellar nuclei, and further characterize the extent of brain degeneration. This study confirmed that vestibulocerebellar, spinocerebellum and pontocerebellar are consistent targets of the pathological process of SCA6, but the severity of neurodegeneration in each of them was different. Vestibulocerebellum and the inferior cerebellar peduncle undergo the most severe neurodegeneration, while neurodegeneration in the pontocerebellar is less severe. Furthermore, we observed obvious neurodegeneration in layers II and III of the primary motor cortex, vestibular nuclei, inferior olivary nucleus, nucleus proprius and posterior spinocerebellar tract. Our detailed postmortem findings confirmed that SCA6 was not a simple "pure" cerebellar disease, but a complex neurodegenerative disease in which the three cerebellar regions underwent different evolutions of neurodegeneration process, and the corresponding precerebellar nuclei and the neural pathway were all involved.

Background In the current study, as a first step to develop a monitoring method of cerebellar functions, we tried to record evoked potentials on the cerebellar cortex by electrical stimulation of the rat SCT, which is located in the Inf-CPed. Methods The experimental study was performed on rats. Unilateral muscular contractions of quadriceps femoris muscle were elicited by electrical stimulation. The evoked potentials were recorded from the surface of the ipsilateral cerebellum and the contralateral primary sensory cortex. Results The highly reproducible potentials obtained from the ipsilateral cerebellar hemisphere were named SCEP. The SCEP exhibited one negative peak with a latency of 11.7 ± 0.3 milliseconds (N 11 ). Short-latency somatosensory evoked potential was recorded from the contralateral primary sensory cortex with a latency of 19.1 ± 0.6 milliseconds. Coagulation of the ipsilateral Inf-CPed caused disappearance or marked reduction of the SCEP N 11 , but it did not change the SSEP. On the other hand, sectioning of the ipsilateral dorsal column resulted in the disappearance of the SSEP, but it did not affect the SCEP N 11 . Conclusions Reproducible SCEP was recorded from the rat cerebellar hemisphere by electrical stimulation of the quadriceps femoris muscle. We posit that the SCEP differs from the SSEP, which ascends via the dorsal column, and that it is conducted by the dorsal SCT located in the Inf-CPed. Our results suggest that it may be possible to detect the dysfunction of the Inf-CPed electrophysiologically by using SCEP.

Background: A presentation of all aspects of the dorsolateral medulla oblongata syndrome is clinically very rare to find. In most cases patients present with fragmentary symptoms, e.g. ipsilateral axial lateropulsion, nystagmus, dysarthria, dysphagia or hemiataxia. However, the clinical presentation and lesion anatomy at the level of the medulla oblongata is still unsatisfactory. The aim of this study was to correlate the functional deficit with structural MRI-data. Methods: We included thirteen patients (eight male, five female, mean age 65.5) with medulla oblongata infarction with clinically predominant ipsilateral axial lateropulsion and correlated clinical with structural deficits. Results: Magnetic resonance imaging lesion mapping demonstrated ipsilateral axial lateropulsion to result from lesions of the spinocerebellar tract, the inferior cerebellar peduncle or the inferior vestibular nucleus. Nystagmus was associated with lesions of the inferior vestibular nucleus, dissociated sensory loss with the spinothalamic tract and hemiataxia with the spinocerebellar tract. Conclusions: Correlating dysfunction and lesion anatomy is a promising approach to enhance our knowledge on medulla oblongata topography.

Inherited ataxias and hereditary spastic paraplegias are two heterogeneous groups of neurodegenerative disorders with a wide spectrum of clinical symptoms and also, with a remarkable number of involved loci/genes. Inherited ataxias are clinically characterized by progressive degeneration of cerebellum and spinocerebellar tracts of the spinal cord associated with a variable combination of signs of central and peripheral nervous system. Hereditary spastic paraplegias (HSPs) are characterized by slowly progressive spasticity and weakness of lower limbs, due to pyramidal tract dysfunction. The classification of these diseases is extremely difficult because of overlapping symptoms among different clinical forms. For this reason, the genetic classification for both inherited ataxias and HSP forms, based on the causative loci/genes has reached general acceptance. The aim of this review is to summarize the genetics and the pathogenic mechanisms involved in these two groups of neurodegenerative spinocerebellar disorders.

Publisher Summary This chapter focuses on the application of cerebellar stimulation in the treatment of epilepsy. The cerebellum can be divided into the flocculonodular, anterior, and posterior lobes. Functional divisions include the vermis, the intermediate zone, and the lateral zone. The flocculonodular lobe coordinates balance and eye movements and the anterior cerebellum is involved in muscle tone and proprioception via the spinocerebellar tracts. Cerebellar stimulation has been previously reported in the treatment of cerebral palsy, spasticity, dystonia, and epilepsy. Pioneering work in the area of cerebellar stimulation began with animal studies that demonstrated that stimulation of the anterior vermis leads to an inhibition of decerebrate rigidity. The animal studies on EEG suppression were confirmed in a human trial that demonstrated that stimulation of the cerebellar dentate nucleus suppressed the subclinical epileptic discharges from intracerebral electrode. For instance, it was demonstrated that stimulation of the cerebellar dentate nucleus suppressed subclinical epileptic discharges on EEG recordings from intracerebral electrodes and correlated with the reduction of the frequency of generalized, complex partial, and secondary generalized seizures. The most common method of electrodes placement is via two suboccipital burr holes, as opposed to a suboccipital craniotomy for exposure of the posterior fossa and the most common placement of electrodes is the superomedial cerebellar cortex.

The projection of the spinocerebellar tract arising from the central cervical nucleus was examined by the anterograde transport of wheatgerm agglutinin or cholera toxin subunit B (choleragenoid) conjugated to horseradish peroxidase in the rat. Following bilateral injections of the tracers into the C1–C3 segments, labeled terminals were seen in lobules I–VI, sublobule VIIb, lobule VIII, sublobule IXa + b and the copula pyramidis. The labeled terminals were densely distributed in the basal half or basal two thirds of lobules I–III in their apicobasal extent, and the transitional areas between the neighboring lobules. The projection field in the horizontal plane of the lobules was reconstructed from a series of transverse sections through each lobule. In the anterior lobe, labeled terminals were distributed in 3 longitudinal areas, named areas 1, 2 and 3, respectively. These areas were confined in the basal half to the basal two-thirds of lobules II and III; area 1 was located in zone A1 of Voogd (within 250 μm of the midline); area 2 was located in zones A1–A2 (about 250 μm lateral to the midline); and area 3 was located in the lateral part of zone A2 to zone B (between 0.5 and 1.0 mm lateral to the midline). In lobule II, another area (area 4) was present lateral to the vermis. In lobule I the 3 longitudinal areas extended over the apicobasal length of the lobule. In sublobule IXa + b and lobule VIII, 4 ill-defined longitudinal areas appeared in the basal two-thirds. The present study confirmed that the projection pattern of the central cervical nucleus is identical in both the rat and the cat.

Functional properties of a crossed spinocerebellar tract with cell bodies located in laminae VII and IX of the S1 segment were investigated using intracellular recording. The neurones were found to be excited by group I and II muscle afferents and afferents of skin, joint and interosseus nerves. Volleys from group II muscle afferents and cutaneous afferents evoked inhibition in these cells. It is concluded that S1 spinocerebellar neurones convey a similar type of information to that of dorsal spinocerebellar tract and ventral spinocerebellar tract neurones but integrate it in a different way.

We report a 37-year-old male without any family history of neurological disease who suffered progressive muscular atrophy and sensory impairment of 4 years' duration. Autopsy revealed neuronal loss in the anterior horns of the spinal cord and in the hypoglossal and facial nuclei of the brain stem. The corticospinal tracts of the spinal cord showed only mild degeneration. In addition, there were obvious degenerative lesions manifested by loss of neurons, myelin and axons in the spinal posterior columns, Clarke's column, spinocerebellar tracts and dorsal root ganglia as well as in the subthalamic nucleus, globus pallidus, substantia nigra and cerebellar dentate nucleus. Furthermore, we frequently encountered Bunina bodies not only in the lower motor neurons but also in the subthalamic neurons. We consider this case to be an atypical example of motor neuron disease with features of multisystem degeneration. The fact that Bunina bodies were observed in both lower motor and subthalamic neurons in this case suggests a common etiology of neuronal degeneration in these two different systems.

At spinal levels, sensory information pertaining to body positioning (proprioception) is relayed to the cerebellum by the spinocerebellar tracts (SCTs). In the past we revealed the basic helix-loop-helix transcription factor Atoh1 (Math1) to be important for establishing Dorsal Progenitor 1 (DP1) commissural interneurons, which comprise a subset of proprioceptive interneurons. Given there exists multiple subdivisions of the SCT we asked whether Atoh1 may also play a role in specifying other cell types in the spinal cord. Here, we reveal the generation of at least three DP1 derived interneuron populations that reside at spatially restricted positions along the rostral–caudal axis. Each of these cell populations expresses distinct markers and anatomically coincides with the cell bodies of the various subdivisions of the SCT. In addition, we found that as development proceeds (e.g. by E13.5) Atoh1 expression becomes apparent in the dorsal midline in the region of the roof plate (RP). Interestingly, we find that cells derived from Atoh1 expressing RP progenitors express SSEA-1, and in the absence of Atoh1 these progenitors become SOX9 positive. Altogether we reveal the existence of multiple Atoh1 dependent cell types in the spinal cord, and uncover a novel progenitor domain that arises late in development.

The paths of embryonic chick spinal commissural neurons originating from the lumbosacral (LS) 2 spinal segment and born around Hamburger-Hamilton stage (HH) 18 were observed by labeling the axons with an in ovo electroporation method designed to limit the electroporated area to similar to one somite length. After crossing the floor plate, these axons followed two major paths, one ventral and one dorsal, and a minor path running between the major ones. These axons reached the brachial region by HH28, passed through the cervical region at HH29, and entered the medullary area by HH30. The dorsal axons entered the developing cerebellum by HH33, crossed the midline again, and spread into the rostralipsilateral area of the developing cerebellum so that most of them were confined to lobules II-III by HH39. A small population of ventrally running axons turned to enter the cerebellum, and the rest entered the superior medullary velum between the cerebellum and the midbrain. The LS2-originating axons that ascended ipsilaterally into the cerebellum followed a single path, and their extension was delayed compared with that of the commissural axons. Some of the ipsilateral axons innervated the cerebellum; the rest entered the superior medullary velum. These direct observations of the formation of part of the spinocerebellar projections in chick will be a useful reference for future analyses of the underlying mechanisms. (c) 2008 Elsevier B.V. All rights reserved.

The distribution of axonal spheroids was examined in the central nervous system of gracile axonal dystrophy (GAD) mutant mice. Only few spheroids are observed in the gracile nucleus of the medulla in normal mice throughout the period examined, while they are first noted in GAD mice as early as 40 days after birth. The incidence of spheroids shifts from the gracile nucleus to the gracile fasciculus of the spinal cord with the progress of disease, suggesting that the degenerating axonal terminals of the dorsal ganglion cells back from the distal presynaptic parts in the gracile nucleus, along the tract of the gracile fasciculus, toward the cell bodies in the dorsal root ganglion. This phenomenon indicates that the distribution of spheroids is age dependent and reflects a dying-back process in degenerating axons. In addition to the gracile nucleus and the gracile fasciculus, which is one of the main ascending tracts of primary sensory neurons, it was noted that the other primary sensory neurons joined with some of the second-order neurons at the dorsal horn and neurons at all levels of the dorsal nucleus (Clarke's column) are also severely affected in this mutant. The incidence of the dystrophic axons are further extended to the spinocerebellar tract and to particular parts of the white matter of the cerebellum, such as the inferior cerebellar peduncle and the lobules of I-III and VIII in the vermis. These results indicate that this mutant mouse is a potential animal model for human degenerative disease of the nervous system, such as neuroaxonal dystrophy and the spinocerebellar ataxia.

The selective involvement of spinocerebellar neurons in sporadic amyotrophic lateral sclerosis was investigated using two monoclonal antibodies that have neuronal subset specificity in human spinal cord. In normal control subjects, monoclonal antibody 6A2 showed specificity for neurons of the dorsal nucleus of Clarke, the cells of origin of the dorsal spinocerebellar tract. Immunoreactive neurons were also observed in locations corresponding to the central cervical nucleus and spinal border region, containing neurons of the cervicospinocerebellar and ventral spinocerebellar tracts, respectively. The latter two neuronal subsets are indistinguishable from surrounding neurons when conventional histological stains are used. Antigen 6A2 was distributed on surfaces of neuronal somas and proximal neurites and extended into the extracellular space. A second antibody, monoclonal antibody 44.1, labeled the cytoplasm of neuronal somas and neurites, including all monoclonal antibody 6A2-reactive cells and alpha motoneurons. In spinal cords of all 5 patients with amyotrophic lateral sclerosis, monoclonal antibody 6A2 reactivity in the majority of spinocerebellar neurons was absent or localized to the somal cytoplasm, which still stained with monoclonal antibody 44.1. In more severely involved tissues, there was loss of some spinocerebellar neurons and a corresponding loss of monoclonal antibody 44.1 reactivity. These findings confirm involvement of the spinal cord components of the spinocerebellar system at all levels in sporadic amyotrophic lateral sclerosis and suggest that some surface molecules are modified during the degenerative process.

Friedreich ataxia (FA) is the most common autosomal recessive disorder of the cerebellum, causing degeneration of spinal sensory neurons and spinocerebellar tracts. The disease is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron metabolism. We tested an experimental model generated by Dr. Puccio's group by crossing mice homozygous for a conditional allele of the Fxn gene with mice heterozygous for a deleted exon 4 of Fxn carrying a tissue-specific Cre transgene under control of the muscle creatine kinase promoter. Relative to wild-type, the MCK-Cre conditional mutants were impaired on tests of motor coordination comprising horizontal bar, vertical pole, and the rotorod as well as displaying gait anomalies and the hindlimb clasping response. Thus this MCK-Cre model reproduces some key features of muscle dysfunction in patients with Friedreich ataxia and provides an opportunity of ameliorating their symptoms with experimental therapies.

We describe a new family with adult onset amyotrophic lateral sclerosis (FALS), in which the disease was characterized clinically by relatively rapid progression of bulbar symptoms. Gene analysis of Cu/Zn superoxide dismutase (SOD1) performed in one patient showed no mutations. Autopsy of another patient demonstrated degenerative changes restricted to the upper and lower motor neuron systems; no evident changes were observed in the posterior column, Clarke's column or spinocerebellar tracts. The presence of Bunina bodies and ubiquitin-positive skein-like inclusions in the lower motor neuron was of considerable interest. Cases of FALS with such pathological features are quite rare in the literature. Identification of the gene responsible for the disease is desirable in order to shed further light on the molecular pathology of not only familial, but also sporadic, ALS.

Objective: To determine the clinical and radiologic features of Gerstmann–Straussler–Scheinker syndrome caused by Pro102Leu mutation in PRNP (GSS102). Methods: The authors report 11 patients (nine families) with clinically and radiologically diagnosed GSS102. Results: All patients showed mild gait disturbance, dysesthesia and hyporeflexia of the lower legs, and truncal ataxia, and 9 of 11 patients showed proximal leg muscle weakness during the early stage of the disease. Dementia was not a main symptom during the early stage. Brain MRI and EEG abnormalities were not prominent initially. SPECT (N-isopropyl-p-[123I]iodoamphetamine) analyzed by the three-dimensional stereotactic surface projection (SSP) method detected abnormalities in five patients early during the course of the illness. SPECT findings showed diffusely decreased cerebral blood flow, demonstrated by a mosaic pattern, with the lowest perfusion noted in the occipital lobes. In contrast, blood flow to the cerebellum was preserved. These studies suggested sites of pathology in GSS102, with the main lesions probably located in the cerebrum and the spinal cord (posterior horn and spinocerebellar tract) instead of the cerebellum. Conclusions: Key features for early diagnosis of Gerstmann–Straussler–Scheinker syndrome caused by Pro102Leu mutation in PRNP (GSS102) are truncal ataxia, dysesthesia and hyporeflexia of the lower legs, and mild dysarthria. Normal cerebellar MRI and abnormal cerebral SPECT findings are characters of early GSS102.

The dorsal spinocerebellar tract (DSCT) provides a major mossy fiber input to the spinocerebellum, which plays a significant role in the control of posture and locomotion. Recent work from our laboratory has provided evidence that DSCT neurons encode a global representation of hindlimb mechanics during passive limb movements. The framework that most successfully accounts for passive DSCT behavior is kinematics-based having the coordinates of the limb axis, limb-axis length and orientation. Here we examined the responses of DSCT neurons in decerebrate cats as they walked on a moving treadmill and compared them with the responses passive step-like movements of the hindlimb produced manually. We found that DSCT responses to active locomotion were quantitatively different from the responses to kinematically similar passive limb movements on the treadmill. The differences could not be simply accounted for by the difference in limb-axis kinematics in the two conditions, nor could they be accounted for by new or different response components. Instead, differences could be attributed to an increased relative prominence of specific response components occurring during the stance phase of active stepping, which may reflect a difference in the behavior of the sensory receptors and/or of the DSCT circuitry during active stepping. We propose from these results that DSCT neurons encode two global aspects of limb mechanics that are also important in controlling locomotion at the spinal level, namely the orientation angle of the limb axis and limb loading. Although limb-axis length seemed to be an independent predictor of DSCT activity during passive limb movements, we argue that it is not independent of limb loading, which is likely to be proportional to limb length under passive conditions.

The course of retrogradely labeled spinocerebellar fibers in the ventral and lateral funiculi of the spinal cord was studied following injections of wheat germ agglutinin-conjugated horseradish peroxidase into the posterior spinocerebellar termination area in the cat. Fibers labeled from unilateral injections into the paramedian lobule were found on the same side in the dorsal part of the lateral funiculus (DLF), corresponding to the dorsal spinocerebellar tract (DSCT), but contralaterally in the ventral part of the lateral funiculus (VLF) and in the ventral funiculus (VF), corresponding to the ventral spinocerebellar tract (VSCT). Following injections into the posterior vermis, labeled fibers were less numerous. Most of them were found in the DSCT and only very few in the VSCT. Previously identified cells of origin of these spinocerebellar tracts were labeled in these experiments and counted. They correlated well with the extents and the locations of the injections that had been made into the two termination sites. These results represent novel detailed information on the location of axons projecting to the two main posterior spinocerebellar termination sites in the spinal white matter in the cat.

Publisher Summary Spinocerebellar ataxia type 5 (SCA5) is a slowly progressive autosomal dominant ataxia that predominantly affects the cerebellum. Although the mutation has not yet been identified, dramatic intergenerational changes in severity and age of onset suggest the possibility that a microsatellite expansion may be involved. Symptoms, which progress over time, include in coordination of the upper extremities, slurred speech, and gait ataxia. SCA5 predominantly affects the cerebellum while largely sparing the brainstem and spinocerebellar tracts. The predominant cerebellar involvement and mild disease course of SCA5 are similar to SCA6. Raw sequence data, recently available from the Human Genome Project, has helped to develop hundreds of microsatellite markers and to create a more detailed map of the region.

By computerized static posturography with sway frequency analysis, subclinical effects of lead on postural balance was examined in 29 female workers (lead workers) employed at a glass factory for 3-17 (mean 7.9) years in Beijing, China, in relation to brainstem function assessed by brainstem auditory evoked potential (BAEP). Their blood lead concentrations ranged from 26 to 79 (mean 55.7) microg/dl; ages were 21-30 (mean 28) years. Control subjects, aged 22-29 (mean 27.0) years, were 14 healthy female workers at a textile factory located in the same district. With eyes closed, power of the sway of high (2-4 Hz) and low (1 Hz or less) frequencies in lead workers was significantly larger than that in controls; with eyes open, their power of the sway of low frequency was significantly larger (p

We examined the characteristic clinical features of one family of familial amyotrophic lateral sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase-1 (SOD1). The disease duration for this family was 18.1 +/- 13.2 (mean +/- S.D.) years, with the age at onset being 39.7 +/- 10.5 years old (mean +/- S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the lower limb of the other side. A wheel chair became necessary at 9.8 +/- 3.2 years after the onset. Upper limb weakness started at 15.5 +/- 8.9 years following from the onset. An autopsy was performed on a 71-year-old woman of the family with the mutation. Her disease duration was 47 years, and she died of pneumonia. She had no clear upper motor neuron involvement. Bulbar sign and respiratory muscle weakness had developed 2 years before her death. Neuropathological findings showed degeneration of corticospinal tracts, anterior/posterior spinocerebellar tracts, posterior columns, and Clarke's columns. There were few anterior horn cells in the lumbar spinal cord and no Lewy body-like hyaline inclusion bodies in these remaining anterior horn neurons. This is the first autopsy report of FALS with a His46Arg mutation in the SOD1 enzyme.

In spinal cord stimulation (SCS) large diameter cutaneous (Abeta) fibres in the dorsal columns (DCs) are activated and have an inhibiting effect on the transmission of pain signals by Adelta and C fibres from the corresponding dermatome(s). The largest Abeta fibres can be activated up to a maximum depth of about 0.25 mm in the DCs. No data are available on the distribution of the large fibres in this superficial human DC layer at the common SCS levels Th(10-11). Such data are indispensable to improve the predictive capability of a computer model of SCS. The whole myelinated fibre population in the superficial 300 microm of the dorsal column (DC(0-300)) at Th(10-11 )of two human subjects was morphometrically analysed. Some data was obtained from a third subject. The superficial dorsolateral column (DLC(0-300)) was included in this analysis because it was hypothesized that large dorsal spinocerebellar tract fibres could also be activated by SCS. Only very few fibres larger than 10.7 microm were found: a mean of 68 (0.5%) in DC(0-300) and 114 (2%) in DLC(0-300). Considering that the effect of SCS is primarily attributed to activation of these largest fibres, it is concluded that a surprisingly small average amount of 2.4 fibres per running 0.1 mm width and 6 fibres per segmental division of the DC is involved. Distinct mediolateral heterogeneity in fibre composition was found in both DC(0-300) and DLC(0-300). In the DC(0-300), the mean diameter of fibres > or =7.1 microm increases significantly by 5% from medial to lateral. Density (i.e. number of fibres per 1000 microm(2)) and frequency (i.e. percentage of a fibre size group compared to its parent population) of the large fibres increase significantly from medial to lateral in the DC(0-300). For fibres > or =10.7 microm, these parameters increase by 200 and 269%, respectively. It is concluded that the difference in stimulation threshold of large Abeta fibres in the median and lateral DC can be mainly attributed to the absence and presence, respectively, of collaterals at the stimulation site. Marked differences were found between DC(0-300) and DLC(0-300). The largest DLC(0-300) fibres (> or =10.7 microm) have a 320% higher frequency and a 473% higher density. Their mean diameter is, however, only 2% larger. The largest DLC(0-300) fibres are not likely to be recruited by SCS, since they are not larger than their DC(0-300) counterparts, they lack collaterals (which would reduce the threshold stimulus substantially) and they are more remote from the stimulation electrode.

Dorsal spinocerebellar tract (DSCT) neurons transmit sensory signals to the cerebellum that encode global hindlimb parameters, such as the hindlimb end-point position and its direction of movement. Here we use a population analysis approach to examine further the characteristics of DSCT neuronal responses during continuous movements of the hind foot. We used a robot to move the hind paw of anesthetized cats through the trajectories of a step or a figure-8 footpath in a parasagittal plane. Extracellular recordings from 82 cells converted to cycle histograms provided the basis for a principal-component analysis to determine the common features of the DSCT movement responses. Five principal components (PCs) accounted for about 80% of the total variance in the waveforms across units. The first two PCs accounted for about 60% of the variance and they were highly robust across samples. We examined the relationship between the responses and limb kinematic parameters by correlating the PC waveforms with waveforms of the joint angle and limb axis trajectories using multivariate linear regression models. Each PC waveform could be at least partly explained by a linear relationship to joint-angle trajectories, but except for the first PC, they required multiple angles. However, the limb axis parameters more closely related to both the first and second PC waveforms. In fact, linear regression models with limb axis length and orientation trajectories as predictors explained 94% of the variance in both PCs, and each was related to a particular linear combination of position and velocity. The first PC correlated with the limb axis orientation and orientation velocity trajectories, whereas second PC with the length and length velocity trajectories. These combinations were found to correspond to the dynamics of muscle spindle responses. The first two PCs were also most representative of the data set since about half the DSCT responses could be at least 85% accounted for by weighted linear combinations of these two PCs. Higher-order PCs were unrelated to limb axis trajectories and accounted instead for different dynamic components of the responses. The findings imply that an explicit and independent representation of the limb axis length and orientation may be present at the lowest levels of sensory processing in the spinal cord.

Publisher Summary This chapter discusses the features of Friedreich's ataxia (FRDA) including clinical features, pathological features, and genetic features. Friedreich's ataxia usually presents in adolescence and clinical features includes a progressive limb and gait ataxia, absence of deep-tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. Pathologically the most obvious findings are loss of large sensory neurones in the dorsal-root ganglia and deterioration of the sensory posterior and Clarke's columns, spinocerebellar tracts, and corticospinal motor tracts of the spinal cord. Effects of FRDA gene mutations are discussed in the chapter. FRDA molecular mechanisms involve iron metabolism, mitochondrial function, and oxidative stress. Clues to the molecular mechanisms underlying FRDA are dominated by the evidence that iron accumulation may be a relatively late event in the disease process, and frataxin may bind iron and either act as a mitochondrial iron store or keep it in a bioavailable form. As such, frataxin may play an important role in the process leading to Fe-S cluster synthesis.

In the cervical and lumbosacral enlargements of the chicken, there are seven spinocerebellar nuclei, the Clarke's column, the spinal border cells, the ventral margin of the ventral horn of both enlargements, and the ventral marginal nucleus in the lumbosacral enlargement. In the present study, we investigated the laterality of spinocerebellar tract axons and the distribution of the spinocerebellar tract neurons projecting into the anterior or posterior part of the cerebellum in these seven nuclei by retrograde transport of wheat germ agglutinin-horseradish peroxidase. The spinocerebellar tract neurons with uncrossed axons were found in the cervical Clarke's column and the cervical spinal border cells, and with crossed ones in the lumbar Clarke's column, lumbar spinal border cells, lumbar lamina IX included in the ventral margin of the ventral horn of the lumbosacral enlargement, and the ventral marginal nucleus. The ventral margin of the ventral horn of the cervical enlargement and lumbar lamina VIII included in the ventral margin of the ventral horn of the lumbosacral enlargement issued spinocerebellar tract axons bilaterally. The spinocerebellar tract neurons of the lumbar spinal border cells and lumbar lamina IX projected to the anterior part of the cerebellum only. And those of the other nuclei projected to both the anterior and posterior parts.

Hereditary spastic paraparesis or Strümpell's disease is a genetically determined neurodegenerative disorder in which the signs and symptoms are predominant in the legs. Inheritance is usually autosomal dominant and in a minority recessive. Neuropathological study reveals a degeneration of the corticospinal tract decreasing from lower lumbar to cervical level and of posterior columns increasing from lumbar to upper cervical level as well as degeneration of the spinocerebellar tracts in approximately 50%. The nature of this nucleo-distal central axonopathy and clinicopathological discrepancy for posterior columns, as well as the limits of the pathological process are poorly understood.

observed in the dorsal funiculi (Fig. 2). In the gray matter, loss of neurons with rarefaction of the neuropile was mild and irregular in distribution. Cranial to the compression site, white matter lesions were located mainly in the dorsal funiculi and, to a lesser degree, in the superficial portions of the dorsolateral funiculi (spinocerebellar tracts) of the cranial part of the C1 segment and in the dorsal fasciculi of the caudal medulla. Caudal to the compression site, lesions were seen mainly in the ventral and lateral funiculi. Microscopic lesions were not observed in the viscera. Bones were not examined histologically. Causes of paresis/paralysis in pigs include epidural and vertebral abscesses,4 vertebral fractures,2 fibrocartilaginous embolism,5 and selenium toxicosis.8 In a previous study, osteophytes were found in the lumbar vertebrae of adult boars, but they did not cause vertebral canal stenosis.3 Vertebral fractures have been associated with lactation osteoporosis,6 electrocution,1 and suppurative spondylitis.2 Lumbar vertebral abscesses with or without vertebral fracture is the most frequent cause of paresis/paralysis diagnosed in pigs submitted to this laboratory. Based on the age of the animal and on the gross and microscopic lesions, the lesions were considered the result of a primary developmental anomaly of the atlanto-occipital joint with consequent degenerative osteoarthropathy, osteophyte formation, and compressive myelopathy. Cervical vertebral malformations with spinal cord injury have been described in many species; they represent a common cause of neurologic disease in horses and dogs.7 A similar condition has not been previously reported in swine. Acknowledgements. We thank Susan Toye, Marco Langlois, and Jules Deslandes for technical assistance.

The reported results demonstrate that monoamines modulate activity of three populations of spinocerebellar tract neurons that are rhythmically active during locomotion. However, information on dynamic changes in muscle length and tension (signaled by muscle spindle primary afferents and tendon organs) and on the absolute length of muscles (signaled by muscle spindle secondary afferents) is differently modulated. The transfer of the former is facilitated but that of the latter is either facilitated or depressed; it is facilitated via Clarke's column dorsal spinocerebellar tract neurons and depressed via dorsal horn dorsal spinocerebellar tract neurons. The effects of noradrenaline and serotonin are similar.

Spinocerebellar fibers originate from neurons in the medial part of lamina VII, including Stilling's sacral nucleus, the lateral part of lamina V, and the ventrolateral part of the ventral horn in the lowest lumbar (L6) and sacral-caudal segments. By using the anterograde transport of biotinylated dextran in the rat, this study examined whether these spinocerebellar fibers project to the cerebellar nuclei. Anterogradely labeled axons that originated from the L6-caudal segments ascended contralaterally through the superficial layer of the lateral cord and entered the cerebellum through the superior cerebellar peduncle and the restiform body. Labeled terminals were bilaterally seen in the medial nucleus and the anterior and posterior interpositus nucleus. They were most numerous contralaterally in the anterior interpositus nucleus. In the anterior interpositus nucleus, they were distributed mainly in the most ventral part at rostral levels and in small numbers in the medial part. In the medial nucleus, labeled terminals were seen in limited rostromedial parts of the middle and the caudomedial subdivision. Only a small number of labeled terminals were seen in the caudomedial part of the posterior interpositus nucleus. The present study shows that the spinocerebellar fibers originating from the lowest lumbar and sacral-caudal segments project to specific areas of the anterior interpositus and the medial nucleus. This finding suggests that the neurons of origin convey information from muscles, joints, and integument to the cerebellar cortex and nuclei, in relation to movement of the hindlimbs. J. Comp. Neurol. 404:21–32, 1999. © 1999 Wiley-Liss, Inc.

Correlation between respiratory movement and neural discharges of antidromically identified 20 crossed spinocerebellar tract (SCT) neurones in the T8-11 segments was examined in the anaesthetized, paralysed cat. Activity of 11 neurones of them was related to phrenic nerve activity; 7 neurones increased and 4 decreased their activity during the active phase of the phrenic nerve. Their rhythmic activity remained even after artificial ventilation was turned off, indicating the central genesis of their rhythmic activity. By comparing discharge patterns with the ventilator on and off, it is suggested that half of these crossed SCT neurones appear to receive additional inputs from the periphery. Neurones which increased their firing rate during phrenic nerve activity tend to respond with decrease discharge to passive chest inflation, and vise versa.

A form of autosomal recessive spastic ataxia unique to the Charlevoix–Saguenay area was clinically identified 20 years ago in patients from that region. This region of Quebec, Canada, was once considered a genetic isolate. First noted at gait initiation, signs of ataxia slowly progress along with spasticity of the four limbs, slurred speech, and followed by distal amyotrophy. Early diagnosis relies on the presence of prominent myelinated fibers embedding retinal blood vessels at funduscopy and marked saccadic alteration of ocular smooth pursuit. Imaging of the posterior fossa shows cerebellar vermis atrophy and nerve conduction studies reveal loss of sensory and reduced motor conduction velocities. The clinical features are consistent with a developmental defect in myelination of both retinal and peripheral nerve fibers. The cause of this defect and the progressive axonal degeneration in the corticospinal and spinocerebellar tracts, as well as in the peripheral nerves is still unknown. Results of recent molecular genetic linkage analysis have located the gene locus to chromosome 13q12. Further research is needed to define where this hereditary spastic ataxia stands in the classification of the early onset spinocerebellar degenerations.

Spinocerebellar projections from the cervical enlargement originate from neurons in the medial part of lamina VI and the central part of lamina VII. In the present study, the topographic projections of the cervical enlargement to the cerebellar nuclei were examined by anterograde tracing with biotinylated dextran in the rat. Following injections of the tracer into the spinal cord at levels between the C5 and T1 segments, anterogradely labeled axons and terminals were immunohistochemically demonstrated in the cerebellar nuclei. Unilateral injections revealed that projections are bilateral, but predominantly ipsilateral, to the cells of origin. Labeled axons entered the media nucleus from its rostrodorsal and rostromedial aspects. Labeled terminals were distributed to dorsal and medial parts of the middle subdivision at its rostral levels and to medial parts of the caudomedial subdivision of the medial nucleus. Most axons terminated in the middle subdivision. Single axons were seen to course rostrocaudally in the medial nucleus and give off terminal axons to both subdivisions. A few labeled terminals were seen in the dorsolateral protuberance of the medial nucleus, and in the anterior interpositus and the posterior interpositus nuclei. No labeled terminals were seen in the lateral cerebellar nucleus. The present study demonstrates that spinocerebellar neurons in laminae VI and VII of the cervical enlargement project to dorsomedial areas of the medial nucleus at rostral levels, bilaterally but predominantly ipsilaterally. It is suggested that these areas specifically receive cutaneous and muscular input related to the forelimb movement.

Study Design This study traced the location, extent, and pathway of sensory feedback after the mechanical stretching of a lateral spinal ligament in young chickens. The pathway was traced by locating the sites of Fos protein production in neuronal cell bodies at various sites in the nervous system. Objectives To trace the location, extent, and pathway of sensory feedback after the mechanical stretching of a lateral spinal ligament in young chickens. Summary of Background Data The innervation of ligaments is thought to form part of a protective feedback mechanism to provide stability for joints. The precise pathway and extent of the feedback for spinal ligaments is currently unknown. Such information would provide a clear focus for future studies, especially for diseases such as scoliosis where it has been suggested that there is abnormality in perception of sensory feedback. Methods The intertransverse ligament on the right side at T3-T4 in 4-week-old chickens was exposed by blunt dissection. After Fos production resulting from the surgery had been stopped, the ligament was stretched mechanically and repeatedly for 60 minutes using a 300-g weight. Various areas of the nervous system then were sectioned and processed immunohistochemically to identify areas of Fos production in nerve cell bodies. The presence of Fos indicated neurons that had been stimulated by the stretching the ligament, including interneurons along the feedback pathway. Results Fos protein was identified in nerve cell bodies in the dorsal root ganglia and intermediate gray matter of the spinal cord at the level of stimulation as well as at several spinal cord levels above and below the site of stimulation. Identification was made on the ipsilateral and the contralateral sides, although the extent of Fos production was less on the contralateral side. Fos presence also was identified in sympathetic ganglia at these sites. Nerve cell bodies in the combined nucleus cuneatus and gracilis in the medulla oblongata, the vestibular nuclei, and the thalamus also contained Fos-positive particles. Conclusions Stretching a single lateral ligament of the spine produces a barrage of sensory feedback from several spinal cord levels on both sides of the spinal cord. This sensory information also is transferred to higher levels in the brain, including the nucleus gracilis and cuneatus, the vestibular nuclei, and the thalamus. These sites of Fos production suggest the locations of pathways for this sensory information, which include the dorsal columns and the spinocerebellar tracts. The information obtained from this study provides a clear focus for future studies in this area, particularly for diseases such as scoliosis where it is thought that incorrect perception of sensory information from the ligaments might be a major contributing factor.

Despite the ability radiologically to image the spinal cord in great detail, history and physical examination remains the basis for the management of patients with disor­ders of the spinal cord. Knowledge of both the external and internal anatomy of the spinal cord is required for accurate interpretation of clinical findings. This chapter will review the important external features of the spinal cord as well as the main clinically relevant white matter tracts and grey matter nuclei. The reader is referred to the chapter on spinal vascular disease (Chapter 24) for details of the blood supply of the cord. In this chapter, the terms anterior and posterior will be used but they are synonymous with ventral and dorsal, respectively.

Why are sensory signals and motor command signals combined in the neurons of origin of the spinocerebellar pathways and why are the granule cells that receive this input thresholded with respect to their spike output? In this paper, we synthesize a number of findings into a new hypothesis for how the spinocerebellar systems and the cerebellar cortex can interact to support coordination of our multi-segmented limbs and bodies. A central idea is that recombination of the signals available to the spinocerebellar neurons can be used to approximate a wide array of functions including the spatial and temporal dependencies between limb segments, i.e. information that is necessary in order to achieve coordination. We find that random recombination of sensory and motor signals is not a good strategy since, surprisingly, the number of granule cells severely limits the number of recombinations that can be represented within the cerebellum. Instead, we propose that the spinal circuitry provides useful recombinations, which can be described as linear projections through aspects of the multi-dimensional sensorimotor input space. Granule cells, potentially with the aid of differentiated thresholding from Golgi cells, enhance the utility of these projections by allowing the Purkinje cell to establish piecewise-linear approximations of non-linear functions. Our hypothesis provides a novel view on the function of the spinal circuitry and cerebellar granule layer, illustrating how the coordinating functions of the cerebellum can be crucially supported by the recombinations performed by the neurons of the spinocerebellar systems., Author Summary The movement control of the brain excels in the seamless coordination of our multi-segmented limbs and bodies and in this respect the brain widely outperforms the most advanced technical systems. So far, however, there is little knowledge about the neuronal circuitry mechanisms by which this coordination could be achieved. The present paper makes a synthesis of some recent findings of cerebellar neuronal circuitry functions and spinocerebellar systems to introduce a novel hypothesis of how the cerebellar and spinal cord neuronal networks together establish signals that form a basis for coordination control in the mammalian central nervous system. The hypothesis takes into account some recent, surprising findings about cerebellar granule cell function and explains some long-standing enigmas concerning the structure of and information mediated by the spinocerebellar pathways. It describes some interesting parallels between the spinocerebellar network and Artificial Neural Networks (ANNs), and capitalizes on some of the major conclusions from ANN studies to explain the biological observations.

Dorsal horn spinocerebellar tract cells of adult rats were labelled by retrograde axonal transport with the B subunit of cholera toxin. Sections were prepared from lumbar and thoracic spinal segments and incubated with antisera which specifically recognise neurokinin-1 receptor protein and substance P. Labelled cells and immunoreactivity for the receptor and substance P were identified by using three different fluorophores and the relationships between them were assessed in single optical sections with three-colour confocal laser scanning microscopy. Forty-eight cells were examined and 23 of them displayed immunoreactivity for the receptor. Many substance P-immunoreactive profiles were present in lamina V and some formed contacts with spinocerebellar tract cells possessing neurokinin-1 receptor immunoreactivity. The evidence suggests that substance P may influence the activity of a subpopulation of dorsal horn spinocerebellar tract cells by acting through neurokinin-1 receptors.

Amyotrophic lateral sclerosis (ALS) remains a syndrome defined by clinical and pathological rather than etiological criteria. The definition includes loss of both upper motor neurons (UMNs), i.e., neurons in motor cortex with secondary degeneration of the corticospinal tracts, and lower motor neurons (LMNs), i.e., neurons in brain stem motor nuclei and anterior horns of the spinal cord. Other neuronal populations such as those of the spinocerebellar tract, dorsal column, and intermediolateral cell column may also be involved in some cases, as assessed by pathological more so than by clinical criteria [95]. The mean duration of survival is 3–4 years with extremes in both directions being encountered. The usual sporadic form of the disease occurs in a male:female ratio of 2–3:1 and has a rather even distribution throughout the world except for several discrete foci in the Western Pacific where incidence rates have been increased up to 1000-fold. In these foci, some of which seem to be disappearing, unique putative neuronotoxic environmental factors are postulated to be involved [58]. The peak incidence rate has usually been regarded as being in the 6th and 7th decade of life, although data from Olmstead County, Minnesota, suggest that incidence rates do not decline after this age [40]. A continued increase in incidence rate would be more consistent with a degenerative disorder than a primary autoimmune or infectious etiology.

Dorsal horn spinocerebellar tract cells were identified according to electrophysiological criteria in adult cats and labelled intracellularly with horseradish peroxidase. Sections containing labelled neurons were processed to reveal serotonin immunoreactivity and examined with light and electron microscopy. Numerous contacts were observed on cell bodies, and on proximal and intermediate parts of dendrites. Electron microscopic examination of contacts revealed that synaptic junctions were usually present at the region of apposition. It is concluded that serotonin has a postsynaptic action on dorsal horn spinocerebellar tract cells and that this action is mediated through conventional synapses.

The ability to electrophysiologically identify the axonal projections of lumbar neurons recorded in chronic unanesthetized intact awake animals is a formidable but essential requirement toward understanding ascending sensory transmission under naturally occurring conditions. Chronic immobilization procedures previously introduced by Morales et al. (1981) for intracellular studies of motoneurons are modified and then integrated with procedures for antidromic cellular identification and extracellular recording of upper (or lower) dorsal lumbar spinocerebellar tract (DSCT) neuronal activity, in conjunction with behavioral state recording and drug microiontophoresis. These implant procedures provide up to 6 months of stable recording conditions and, when combined with other techniques, allow individual DSCT neurons to be monitored over multiple cycles of sleep and wakefulness, following the induction into and recovery from barbiturate anesthesia and/or during the juxtacellular microiontophoretic ejection of inhibitory or excitatory amino acid neurotransmitters. The combination of such techniques allows a comprehensive examination of synaptic transmission through the DSCT and other lumbar sensory pathways in the intact normally respiring cat and its modulation during the general anesthetic state. These techniques permit investigations of the supraspinal controls impinging on lumbar sensory tract neurons during wakefulness and other behavioral states such as active sleep.

Contacts between serotoninergic nerve fibres and dorsal horn dorsal spinocerebellar tract neurons were analysed in order to investigate the morphological basis of actions of serotonin upon dorsal spinocerebellar tract neurons. In a series of experiments dorsal spinocerebellar tract neurons were labelled with intracellularly injected rhodamine-dextran in the cat. The neurons were monosynaptically excited by group II muscle afferents and cutaneous afferents and were identified by antidromic activation following stimuli applied in the cerebellum. In the second series of experiments dorsal spinocerebellar tract neurons were labelled by retrograde transport of Fluorogold injected into the cerebellum in the rat. In both series, serotoninergic fibres were labelled by using a specific anti-serotonin antiserum and were revealed by immunofluorescence. Appositions between the serotoninergic fibres and the cells were inspected with a dual channel confocal microscope. The merged images obtained with the two channels of the microscope were viewed in single optical planes 2 microns apart and in rotated three-dimensional reconstructions. Serotoninergic nerve fibres were found in apposition to cell bodies of all feline dorsal spinocerebellar tract neurons (n = 7) and of 75% of rat dorsal spinocerebellar tract neurons (n = 90). The numbers of putative contacts on cell bodies varied between less than 100 and nearly 300 (mean 160) in the cat and between about five and 30 in the rat. Contacts with dendrites of feline neurons were seen on 96% of 72 dendrites within 300 microns from soma and on 91% of 23 dendrites at distances of 300-500 microns. The number of such contacts varied from less than five to 150 on a single dendrite within these ranges of distances. Their total number within 100 microns from the soma was comparable or exceeded the number of contacts on the soma.

The nucleus caudalis DREZ operation has been performed in three phases at Duke. Between 1982 and 1988 radiofrequency (RF) lesions were made in the trigeminal nucleus extending from the C2 root to the obex using a straight electrode. Complications include ipsilateral arm ataxia due to spinocerebellar tract injury and ipsilateral lower limb weakness from the pyramidal tract. The former occurred at least transiently in 90% of cases. The electrode employed from 1988 to 1989 had proximal insulation protecting the spinocerebellar tract. Since 1989 a ninety degree bend has been added to the electrode to allow better placement. Two electrodes are used to accommodate the shape of the caudalis nucleus. A total of 101 procedures have been performed. The newest electrodes were used in 46 procedures. Ataxia is recognized in 39%. Overall pain relief was excellent in 34% and good in 40%. In post herpetic neuralgia 71% enjoyed excellent or good relief. Indications include post herpetic neuralgia, deafferentation pain (anaesthesia dolorosa, post-tic dysesthesia, stroke, MS, gasserian tumour, Gamma Knife radiation injury), facial trauma/surgery, atypical facial pain, and migraine/cluster headache. A study to compare this operation to deep brain stimulation prospectively for the above indications has been initiated.

Dystonia musculorum (dt) mutant mice, characterized by degeneration of spinocerebellar tracts, were impaired in terms of horizontal and vertical motor activity, hole poking, exploration, and motor coordination. In tests of motor coordination, their deficits were more severe than those of previously tested mutant mice with degeneration of cerebellar cells. However, unlike other cerebellar mutants, dt mutants alternated above chance levels in a two-trial spontaneous alternation test, which is a test of inhibitory tendencies and spatial orientation, and so dt mutants may not be impaired in these functions.

The temporal and spatial neurogenic patterns of spinothalamic and spinocerebellar neurons were determined in spinal cord segment L1 of the rat. Neurogenic patterns were demonstrated with [3H]thymidine administered to fetal rats during the period when neurons with supraspinal projections are known to be generated, i.e. on one of embryonic (E) days E13, E14, or E15. The animals were allowed to survive 50 to 100 days postpartum, then neurons with spinothalamic and spinocerebellar projections were retrogradely filled with fluorescent axonal tracers, Fluoro-Gold or True blue, which were pressure injected into the dorsal thalamus and cerebellum in various combinations in the same and in separate animals. Neurons labeled with each retrograde tracer and [3H]thymidine and neurons labeled with retrograde tracers alone were counted in spinal cord segment L1 in each of the animals. Spinothalamic and spinocerebellar neurons were found to be separate and distinct populations. Statistical analysis of the data showed that spinothalamic and spinocerebellar neurons also have distinctly different patterns of neurogenesis which suggest early determination in each cell line. The temporal neurogenic pattern followed a projection-distance gradient, such that spinothalamic neurons, which have longer axons than spinocerebellar neurons, completed neurogenesis prior to spinocerebellar neurons in each region of the spinal gray.

1. Ascending tract neurones located in the dorsal horn of sacral segments of the spinal cord have been investigated by extracellular and intracellular recording in the anaesthetized cat. The aim was to determine whether information from group II afferents that terminate within the sacral segments is conveyed to supraspinal structures and which types of neurones are involved. 2. A considerable proportion of ascending tract neurones found in the dorsal horn in the same segments as the pudendal (Onuf's) motor nucleus were excited by group II muscle afferents. The great majority (93%) of these neurones had axons ascending in ipsilateral funiculi. Spinocervical tract neurones constituted the largest proportion (82%) of such neurones, while very few spinocerebellar tract and propriospinal neurones and no postsynaptic dorsal column neurones were found among them. 3. In addition to activation by group II muscle afferents all of the neurones were strongly excited by cutaneous afferents. The most potent excitation was evoked by afferents of the posterior biceps-semitendinosus and gastrocnemius muscle nerves and by afferents of the cutaneous femoris, sural and pudendal nerves. The latencies of intracellularly recorded excitatory potentials were indicative of a high incidence of monosynaptic coupling between the afferents and ascending tract neurones. 4. The highly effective monosynaptic excitation of spinocervical tract neurones in the sacral segments by group II afferents is in contrast to the weak disynaptically mediated actions of group II afferents on such neurones in the L6-L7 segments but comparable to the actions of group II afferents on ascending tract neurones in the midlumbar segments. 5. Both the patterns of peripheral input and the latencies of synaptic actions in ascending tract neurones were similar to those in interneurones at the same locations (accompanying report). Similar information is therefore likely to be processed by both categories of neurones. 6. The role of sacral spinocervical tract neurones as a system for transmitting information from group II muscle afferents to supraspinal centres and the potential contribution of this system to the perception of limb position are discussed.

We describe two patients with sporadic amyotrophic lateral sclerosis (ALS), who had developed progressive external ophthalmoplegia of a predominantly supranuclear type while they survived on respirators, and displayed histopathological abnormalities both typical and atypical of ALS. Patient 1 was a 43-year-old man with ALS of 5-year duration, who had initially exhibited fulminant ALS, and remained on a respirator for 4 years. Patient 2 was a 51-year-old man with ALS of 13-year duration, who remained on a respirator for 8 years. Both patients died in a "totally locked-in state". Autopsy of both patients revealed not only histopathological abnormalities consistent with ALS, but also multisystem degeneration which involved the pontine tegmentum, substantia nigra, Clarke's dorsal nuclei and spinocerebellar tracts. In addition, Patient 2 displayed intracytoplasmic neuronal basophilic inclusion bodies which exhibited marked immunoreactivity to anti-ubiquitin antibodies. Our case reports indicate that the longer survival which is possible through the use of respirators may make one subgroup of ALS patients prone to develop atypical clinical and neuropathological features which are not observed during the natural course of ALS.

Spinal afferent fibers have been shown to project both to lobules III-VI and lobule IX of the cerebellum in the pigeon. In the present investigation the cells of origin of these projections and the course of the axons at spinal levels have been studied by the retrograde transport of fluorescent dyes injected into both parts of the cerebellum. In the upper cervical segments labeled neurons are located predominantly in the ventral horn; the axons cross to the contralateral side. In the cervical enlargement labeled neurons concentrate in the avian cervical Clarke's column (ClC) and in cervical "spinal border cells" (SBC). The axons of ClC neurons project ipsilaterally into the dorsolateral funiculus and SBC project ipsilaterally into the ventrolateral funiculus. In caudal cervical and in thoracic segments dorsal horn neurons (laminae IV/V) are at the origin of an ipsilateral spinocerebellar pathway in the dorsalmost part of the lateral funiculus. In the lumbosacral enlargement there are mainly three spinocerebellar cell groups all of which project contralaterally into the ventral funiculus: ClC, SBC and paragriseal cells. During its ascent this pathway shifts to the lateral funiculus. In addition there is a crossed pathway from ventral horn cells throughout the spinal cord. Whereas approximately equal numbers of dorsal horn cells project to lobules III-VI and to lobule IX, the number of ClC neurons is strongly reduced after lobule IX injections and SBC neurons are nearly absent. Altogether lobule IX has a substantial input from dorsal horn neurons (cutaneous mechanoreception) whereas that to lobules III-VI is dominated by ClC and SBC (proprioreception).