Pontocerebellar Fibers Research Articles

Ataxia after pontine stroke: insights from pontocerebellar fibers in monkey.

Basis pontis lacunes cause contralateral but rarely ipsilateral ataxia. We explored this phenomenon with isotope tract tracing in the rhesus monkey. Labeled pontocerebellar fibers cross midline and disperse widely in the opposite hemipons before coalescing in the brachium pontis. This anatomical arrangement suggests that small pontine strokes spare sufficient decussating pontocerebellar fibers to prevent ipsilateral dysmetria, and that ipsilateral dysmetria after large pontine stroke represents a disconnection syndrome.

MRI in Movement Disorder Patients: "Hot cross bun" sign

Clinically, multiple system atrophy is difficult to differentiate from other basal ganglia disorders such as idiopathic Parkinson's disease or other types of cerebellar ataxia. The cross bunsign is a radiological sign which, it has been claimed, is highly specific for multiple system atrophy, and we describe four cases in which this sign occurred. In one patient, multiple system atrophy was clinically diagnosed, but in the other three, the respective clinical diagnosis was spinocerebellar ataxia type 1, type 2 (genetically), and old cerebellar hemorrhage. We therefore suggest that the hot cross bun sign reflects degeneration of transverse pontocerebellar fibers and is not a pathognomic sign of multiple system atrophy.

Crossed cerebellar diaschisis in herpes simplex encephalitis

Diaschisis is extremely rare in patients with viral encephalitis. We report the phenomenon of crossed cerebellar diaschisis (CCD) in a 73-year-old man with acute herpes simplex type-1 (HSV-1) encephalitis. The diagnosis of HSV-1 encephalitis was confirmed by detecting HSV-1 deoxyribonucleic acid in the cerebrospinal fluid (CSF). Magnetic resonance images (MRI) showed enhancing lesions at bilateral temporal lobes, insular cortices, and right frontoparietal lobes. Increase signal intensity on T2-weighted images was seen in the mesecephalon. Technetium-99m ethyl cysteinate dimer ( 99mTc-ECD) single photon emission computed tomography (SPECT) of the brain showed a large area of hypoperfusion in the right frontotemporoparietal lobes. The side-to-side cerebellar count revealed 19% reduction of the radioisotope tracer uptake in the left cerebellum. The phenomenon of CCD was proposed to be due to both anterograde disconnection of the corticopontocerebellar tracts and retrograde deafferentation of dentatothalamocortical projections.

Biochemical evidence of crossed cerebellar diaschisis in terms of nitric oxide indicators and lipid peroxidation products in rats during focal cerebral ischemia

Cerebral hypoperfusion in the contralateral cerebellar hemisphere after stroke is interpreted as a functional and metabolic depression, possibly caused by a loss of excitatory afferent inputs on the corticopontocerebellar pathway terminating in the cerebellar gray matter. This phenomenon is defined as crossed cerebellar diaschisis and can be diagnosed clinically by positron emission tomography, single-photon emission computed tomography, brain magnetic resonance imaging and electroencephalography in terms of regional cerebral blood flow or metabolic rate of oxygen measurements. In the present study, nitric oxide indicators (nitrite and cyclic guanosine monophosphate) and lipid peroxidation products (malondialdehyde and conjugated dienes) were measured in rat cerebral cortices and cerebella after permanent right middle cerebral artery occlusion in order to assess the crossed cerebellar diaschisis. Nitrite values in ipsilateral cortex were significantly higher than those in contralateral cortex at 10 (P < 0.001) and 60 (P < 0.05) min of ischemia but no significant changes were observed in both cerebellum compared to the 0 min values. In both cerebral cortex and cerebellum cGMP levels at 10 and 60 min were significantly increased (P < 0.001). This increase was marked in ipsilateral cortex and contralateral cerebellum when compared with opposite cortex and cerebellum (P < 0.001). MDA values in ipsilateral cortex were significantly higher than those in contralateral cortex at 60 min of ischemia (P < 0.05). Contralateral cerebellar MDA values were found significantly higher than those in ipsilateral cerebellum at 0 (P<0.001) and 60 (P < 0.05) min of ischemia. In ipsilateral cortex, conjugated diene values at 0, 10, 60 min of ischemia were higher than those in contralateral cortex. On the other hand 0, 10, 60 min conjugated diene levels in contralateral cerebellum were significantly higher than those in ipsilateral cerebellum (P < 0.001). These findings support the interruption of the corticopontocerebellar tract as the mechanism of the crossed cerebellar diaschisis.

Roles of neuregulin in synaptogenesis between mossy fibers and cerebellar granule cells.

Neuregulins (NRGs), a large group of structurally related signaling proteins, are likely to have important roles in the development, maintenance and repair of the nervous system and other selected tissues. We have demonstrated, by using the major form of NRG cloned from the mouse cerebellum that both the soluble form and the membrane anchored form of NRG may serve different functions in synaptogenesis. The soluble form of NRG was produced by proteolytic cleavage of the membrane anchored form of NRG. The proteolytic cleavage was promoted by protein kinase activation. The cleaved form of NRG trans-synaptically regulated the expression of the NMDA (N-methyl-D-aspartate) receptor subunit NR2C as neurally-derived factors, whereas the membrane anchored form of NRG showed a homophilic binding activity between NRGbeta1s. In adult mice the membrane anchored form of NRG was concentrated in neuro-terminals of both granule cells and pontocerebellar mossy fibers. The fact that NRG can be functionally viewed as cell recognition molecules as well as neurotrophic agents suggests new possibilities for the important class of molecules.

Involvement of pontocerebellar mossy fibers in the development of cerebellar cortex revealed by analyzing weaver mutant mouse

Involvement of pontocerebellar mossy fibers in the development of cerebellar cortex revealed by analyzing weaver mutant mouse

BDNF and NT4/5 promote survival and neurite outgrowth of pontocerebellar mossy fiber neurons

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and NT4/5 are all found in the developing cerebellum. Granule cells, the major target neurons of mossy fibers, express BDNF during mossy fiber synaptogenesis. To determine whether neurotrophins contribute to the development of cerebellar afferent axons, we characterized the effects of neurotrophins on the growth of mossy fiber neurons from mice and rats in vitro. For a mossy fiber source, we used the basilar pontine nuclei (BPN), the major source of cerebellar mossy fibers in mammals. BDNF and NT4/5 increased BPN neuron survival, neurite outgrowth, growth cone size, and elongation rate, while neither NT3 nor NGF increased survival or outgrowth. In addition, BDNF and NT4/5 reduced the size of neurite bundles. Consistent with these effects, in situ hybridization on cultured basilar pontine neurons revealed the presence of mRNA encoding the TrkB receptor which binds both BDNF and NT4/5 with high affinity. We detected little or no message encoding the TrkC receptor which preferentially binds NT3. BDNF and NT4/5 also increased TrkB mRNA levels in BPN neurons. In addition to previously established functions as an autocrine/paracrine trophic factor for granule cells, the present results indicate that cerebellar BDNF may also act as a target-derived trophic factor for basilar pontine mossy fibers. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 254–269, 1999

BDNF and NT4/5 promote survival and neurite outgrowth of pontocerebellar mossy fiber neurons

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and NT4/5 are all found in the developing cerebellum. Granule cells, the major target neurons of mossy fibers, express BDNF during mossy fiber synaptogenesis. To determine whether neurotrophins contribute to the development of cerebellar afferent axons, we characterized the effects of neurotrophins on the growth of mossy fiber neurons from mice and rats in vitro. For a mossy fiber source, we used the basilar pontine nuclei (BPN), the major source of cerebellar mossy fibers in mammals. BDNF and NT4/5 increased BPN neuron survival, neurite outgrowth, growth cone size, and elongation rate, while neither NT3 nor NGF increased survival or outgrowth. In addition, BDNF and NT4/5 reduced the size of neurite bundles. Consistent with these effects, in situ hybridization on cultured basilar pontine neurons revealed the presence of mRNA encoding the TrkB receptor which binds both BDNF and NT4/5 with high affinity. We detected little or no message encoding the TrkC receptor which preferentially binds NT3. BDNF and NT4/5 also increased TrkB mRNA levels in BPN neurons. In addition to previously established functions as an autocrine/paracrine trophic factor for granule cells, the present results indicate that cerebellar BDNF may also act as a target-derived trophic factor for basilar pontine mossy fibers.

Isolated dysarthria due to extracerebellar lacunar stroke: a central monoparesis of the tongue

OBJECTIVESThe pathophysiology of dysarthria can preferentially be studied in patients with the rare lacunar stroke syndrome of “isolated dysarthria”.METHODSA single study was carried out on seven consecutive patients with sudden...

Disequilibrium in patients with atherosclerosis: relevance of pontine ischemic rarefaction. Amsterdam Vascular Medicine Group.

To examine the clinical relevance of isolated pontine hyperintense lesions (PHLs) on MRI in patients with atherosclerosis. Seventeen atherosclerotic patients with isolated PHL on MRI were compared with 17 patients without PHL and were matched for age, sex, and initial manifestation of atherosclerosis. Subjects and observer were blinded to the MRI findings. We assessed symptoms, impairment, and disability with a structured interview and neurologic examination as well as disability scales. On all items, patients with PHL scored worse than did their controls. We found the largest differences in frequencies of symptoms of disequilibrium, difficulties with speech or swallowing, the Timed Walking Test, and the body care and movement subscale of the Sickness Impact Profile. Except for disequilibrium (p = 0.04), these differences did not reach statistical significance. Abnormal tandem-walking tests were more frequent in patients than they were in controls. Pyramidal signs were equally distributed. We propose PHL as a cause of symptoms of disequilibrium in patients with atherosclerosis. Symptoms are probably elicited by dysfunction of the corticopontine fibers, the pontocerebellar fibers, or the pontine nuclei.

Syndromes of pontine base infarction. A clinical-radiological correlation study.

Although there have been sporadic reports of lacunar syndromes due to pontine base infarction, studies of clinical-radiological correlation in sufficient numbers of patients have not yet been reported. We studied the clinical features of 37 patients with acute infarcts that mainly involved the base of the pons and correlated the clinical syndromes with the radiological findings. The clinical presentations included pure motor hemiparesis (PMH) in 17, sensorimotor stroke in 3, ataxic hemiparesis (AH) in 4, and dysarthria-clumsy hand (DA-CH) syndrome in 6 patients. Variants of AH included 1 patient with dysarthria-hemiataxia and 2 with quadrataxic hemiparesis, and in 4 patients dysarthria-facial paresis syndrome was considered a variant of DA-CH syndrome. Hypertension was the single most common and important risk factor, and the pathogenetic mechanisms of ischemia were likely to be small arterial (lacunar) occlusion or basilar atheromatous branch occlusion in most of the patients. Our clinical-radiological correlation study suggested that large lesions involving the paramedian caudal or middle pons correlate with severe hemiparesis (PMH), whereas lesions of similar size located in the paramedian rostral pons tended to produce DA-CH syndrome. Lesions producing AH were located variously but tended to spare the pyramidal tracts. The prognosis of these patients is fair or good, although residual hemiparesis remained in patients with initially severe hemiparesis. Our data suggest that the various lacunar syndromes that follow pontine base infarcts reflect the balance of the involvement of the corticospinal, corticopontocerebellar, and corticobulbar tracts. Analysis of radiological findings aids in determining the clinical-anatomic correlation in patients with pontine base infarction.

Secondary changes in cerebellar perfusion (diaschisis) in hemiplegia during childhood: SPECT study of 55 children

Diaschisis is a functional impairment at a site in the brain remote from the lesion causing it. An investigation of cerebellar diaschisis in childhood was undertaken to better understand the functional maturation of the corticopontocerebellar tract in developing brain. A retrospective study of cerebellar diaschisis in 55 hemiplegic children was conducted using singlephoton emission computed tomography (SPECT) with 123I-IMP. Cerebellar diaschisis was evaluated by 2 authors. Crossed cerebellar diaschisis (CCD) was found in 6 of 55 patients. SPECT findings of patients who presented with CCD disclosed supratentorial hypoperfusion of varying degrees, from focally to the whole hemisphere; however, patients had frontal and/or parietal hypoperfusion in common. A second type of cerebellar diaschisis also was demonstrated. Cerebellar hypoperfusion ipsilateral to supratentorial lesions, ipsilateral cerebellar diaschisis (ICD), was observed in 10 of 55 patients. CCD occurred in the patients who suffered from brain injuries after 7 years, 5 months of age, while ICD manifested in patients whose brain injuries occurred before 3 years, 1 month of age. The production of remote effects, such as CCD and ICD, could be closely related to maturation of the corticopontocerebellar tract in the developing brain during childhood.

Hemodynamic and metabolic changes in crossed cerebellar hypoperfusion.

The pathophysiology of crossed cerebellar diaschisis remains to be elucidated. The mechanism responsible appears to be deafferentation through the corticopontocerebellar tract, which terminates in the cerebellar gray matter. However, few studies have demonstrated the hemodynamic and metabolic changes in the cerebellar gray matter and pons in crossed cerebellar diaschisis. Using positron emission tomography in 24 patients with unilateral supratentorial stroke, we evaluated regional blood flow, metabolic rate of oxygen, oxygen extraction fraction, and blood volume in the cerebellar cortex and pons. Sixteen patients with significant cerebellar blood flow asymmetry, defined as a percentage difference in blood flow beyond the upper 95% confidence limit defined in eight normal subjects, were selected as the group with crossed cerebellar hypoperfusion. In patients with crossed cerebellar hypoperfusion, the metabolic rate of oxygen was significantly decreased in the cerebellar cortex contralateral to the supratentorial stroke, compared with that in the ipsilateral cerebellar cortex; this decrease was less than the decrease in cerebellar blood flow. The degrees of cerebellar asymmetry in these two parameters were negatively correlated with the metabolic rate of oxygen in the pons. The oxygen extraction fraction was slightly, but significantly, increased. In contrast to the ischemic state, however, the cerebellar blood volume was decreased, with no difference in the ratio of cerebellar blood flow to blood volume. These findings support interruption of the corticopontocerebellar tract as the mechanism of crossed cerebellar hypoperfusion. Our results also suggest a mild elevation in the oxygen extraction fraction in this state, with a mechanism distinct from ischemia.

脳血管障害に伴うｃｒｏｓｓｅｄ ｃｅｒｅｂｅｌｌａｒ ａｔｒｏｐｈｙ

A neuroradiological study of crossed cerebellar atrophy (CCA) was performed using X-ray CT in 103 patients suffering from unilateral supratentorial cerebrovascular diseases. CCA was demonstrated in 9 (8.7%) of 103 patients. No difference between the occurrence of CCA in cerebral hemorrhage and that in cerebral infarction was found. CCA was seen in the chronic stage of cerebrovascular disease more than 3 years since stroke occurrence, and was found to be present more frequently and to a greater extent 7 years later. No correlation between the site of bleeding and the occurrence of CCA was found. Trans-synaptic degeneration of the corticopontocerebellar tract was considered in CCA following putaminal and combined hemorrhage involving an internal capsule lesion. However, in thalamic hemorrhage, retrograde degeneration within the cerebellorubrothalamic tract was presumed. CCA following cerebral infarction was seen in patients with massive lesions in the territory of the middle cerebral artery. Multivariate analysis showed that lesions of the parietal and frontal lobes appeared to greatly contribute to the development of CCA. As the degeneration and atrophy in the thalamus on the side of the lesion appeared early and frequently, it was suggested that retrograde degeneration of the cerebellorubrothalamic tract participated, in addition to anterograde corticopontocerebellar tract degeneration, in CCA following middle cerebral artery infarction. It is likely that CCA is caused by both transsynaptic degeneration of the corticopontocerebellar tract and the cerebellorubrothalamic tract.

Anatomic and Functional Changes Associated with Crossed Cerebellar Diaschisis in Chronic Brain Injured Subjects

The anatomic and functional changes associated with crossed cerebellar diaschisis (CCD) were examined in chronic brain injured patients to determine if there is evidence that injury to a neuroanatomic tract, such as the corticopontocerebellar tract, could explain the cerebellar diaschisis, and to determine if arm movements would effect the CCD. Four brain injured patients and four normal subjects had MR scans and PET scans using fluorodeoxyglucose. The PET scans were obtained during rest and during left and right arm motor tasks. The PET scans were repeated after six months to determine the reproducibility of the scan findings. Forty-one PET scans were analyzed. Significant crossed cerebellar diaschisis was present in all fourbrain injured patients. One control patient had crossed cerebellar diaschisis, but the cerebellar asymmetry was more subtle than noted in the brain injured patients. MR scans demonstrated atrophy of the cerebral peduncle ipsilateral to the major cerebral cortical injury. One patient had bilateral cerebral cortical and cerebral peduncle atrophy. These findings support the hypothesis that injury to the corticopontocerebellar tract may, in part, be responsible for crossed cerebellar diaschisis in chronic brain injured subjects. Key Words: Brain, injuries—Brain, radionuclide studies—Emission CT—Diaschisis—Degeneration, Wallerian.

Do pontocerebellar mossy fibres give off collaterals to the cerebellar nuclei? An experimental study in the cat with implantation of crystalline HRP-WGA

In 15 cats with implantations of crystalline HRP-WGA in the cerebellar nuclei and tetramethylbenzidine histochemistry, the pontine nuclei were carefully examined for presence of retrogradely labelled cells. Findings in the nucleus reticularis tegmenti pontis and the inferior olive, both known to project to the cerebellar nuclei, served as controls for effectiveness of uptake and transport. After implantations restricted to the lateral cerebellar nucleus in 5 cats altogether two labelled cells were found in the contralateral pontine nuclei in regions receiving afferents from the lateral nucleus. In contrast, many labelled cells occurred in the nucleus reticularis tegmenti pontis and the inferior olive. After implantations in 5 cats restricted to the posterior or anterior interposed nuclei, altogether only one labelled cell was found in the pontine nuclei, while many labelled cells occurred in the inferior olive. The nucleus reticularis tegmenti pontis contained a small number of retrogradely labelled cells after implantations in the anterior interposed nucleus, but none after implantations restricted to the posterior interposed nucleus. After implantations restricted to the medial (fastigial) nucleus, no retrogradely labelled cells were found in the pontine nuclei and nucleus reticularis tegmenti pontis (although many were present in the inferior olive). The present findings support earlier conclusions based on anterograde tracing methods that the cerebellar nuclei receive very few, if any, afferents from the pontine nuclei.

Do pontocerebellar mossy fibres give off collaterals to the cerebellar nuclei? An experimental study in the cat with implantation of crystalline HRP-WGA

In 15 cats with implantations of crystalline HRP-WGA in the cerebellar nuclei and tetramethylbenzidine histochemistry, the pontine nuclei were carefully examined for presence of retrogradely labelled cells. Findings in the nucleus reticularis tegmenti pontis and the inferior olive, both known to project to the cerebellar nuclei, served as controls for effectiveness of uptake and transport. After implantations restricted to the lateral cerebellar nucleus in 5 cats altogether two labelled cells were found in the contralateral pontine nuclei in regions receiving afferents from the lateral nucleus. In contrast, many labelled cells occurred in the nucleus reticularis tegmenti pontis and the inferior olive. After implantations in 5 cats restricted to the posterior or anterior interposed nuclei, altogether only one labelled cell was found in the pontine nuclei, while many labelled cells occurred in the inferior olive. The nucleus reticularis tegmenti pontis contained a small number of retrogradely labelled cells after implantations in the anterior interposed nucleus, but none after implantations restricted to the posterior interposed nucleus. After implantations restricted to the medial (fastigial) nucleus, no retrogradely labelled cells were found in the pontine nuclei and nucleus reticularis tegmenti pontis (although many were present in the inferior olive). The present findings support earlier conclusions based on anterograde tracing methods that the cerebellar nuclei receive very few, if any, afferents from the pontine nuclei.

Immunohistochemical localization of glutamate, glutaminase and aspartate aminotransferase in neurons of the pontine nuclei of the rat

The pontine nuclei form the key relay nuclei in the cerebropontocerebellar pathway. Although a great deal of information is available regarding the anatomy of this region, the identity of the neurotransmitter(s) contained in the neurons of the pontine gray are not known. The aim of the present investigation is to utilize immunohistochemical techniques to determine whether glutamate, a putative excitatory transmitter, and the enzymes responsible for its metabolism, are found in pontine neurons. Both glutaminase, an enzyme which converts glutamine to glutamate, and aspartate aminotransferase, an enzyme which is involved in the interconversion between glutamate and aspartate, have been proposed to be markers of neurons which use excitatory amino acids as neurotransmitters. The present study utilizes a monoclonal antibody against carbodiimide-fixed glutamate and polyclonal antisera against glutaminase and aspartate aminotransferase in conjunction with the indirect peroxidase technique or the peroxidase-labeled biotin-avidin procedure to localize glutamatergic neurons in the pontine nuclei of the rat. Numerous neurons in all subdivisions of the pontine nuclei were found to contain carbodiimide-fixed glutamate-like immunoreactivity, glutaminase-like immunoreactivity or aspartate aminotransferase-like immunoreactivity. Horseradish peroxidase was injected into the cerebellum of four rats for use with a combined retrograde transport-immunohistochemical procedure. Double-labeled neurons were observed in all subdivisions of the pontine nuclei, indicating that pontine neurons which contain glutamate-like immunoreactivity project to the cerebellum. Based on the hypothesis that increased levels of glutamate, glutaminase and aspartate aminotransferase reflect a transmitter role for glutamate, the present data raise the possibility that glutamate may be a major neurotransmitter of pontocerebellar fibers.

The cerebellopontine system in the rat. I. Autoradiographic studies.

This study utilized light microscopic autoradiographic procedures to describe the projections from the three major subdivisions of the deep cerebellar nuclei (DCN) to the basilar pontine nuclei (BPN). Although the vast majority of cerebellopontine axons reached the BPN via the descending limb of the brachium conjunctivum (BC) after crossing the midline within the midbrain, a relatively small number of ipsilaterally projecting fibers was also observed. Fascicles of cerebellopontine axons left the main bundle of descending limb fibers throughout much of the rostrocaudal length of the BPN and passed around and through the medial lemniscus and cerebral peduncle to enter the pontine gray. The lateral cerebellar nucleus gave rise to the largest number of cerebellopontine fibers, whose terminal fields exhibited both diffuse and patchlike labeling patterns within each of the major subdivisions of the BPN including medial, ventral, lateral, and dorsal areas. Projections from the interpositus complex exclusive of its posterior division were fewer and less widely distributed than those from the lateral nucleus. Interpositopontine fibers terminated primarily in the caudal one-half of the BPN in medial, ventral, and lateral regions and overlapped somewhat with projections from the lateral cerebellar nucleus. Pontine projections emanating from the medial cerebellar nucleus were the fewest and most restricted in distribution relative to the other two cerebellar efferent systems. Such fibers formed a patchlike network of terminal fields which extended throughout much of the rostrocaudal length of the BPN in medial and dorsomedial regions. A relatively small but considerable number of ipsilateral cerebellopontine fibers terminated in pontine regions, which often mirrored the typical contralateral projection fields. Although it proved difficult to determine the precise origin of the ipsilateral fiber systems, it appeared that each of the three major DCN subdivisions made some contribution. Also it was apparent that considerable overlap existed between cerebellopontine projection zones and those of other pontine afferents including sensorimotor, visual, and auditory cortices, the superior colliculus, and the mammillary nuclei of the hypothalamus. Moreover, cerebellopontine terminal fields were congruent in some instances with discrete clusters of BPN neurons which serve as the source of pontocerebellar fiber systems, reaching portions of the lateral cerebellar hemispheres, posterior vermis, and the paraflocculus.

Do pontocerebellar fibers send collaterals to the cerebellar nuclei?

Three cats received large injections in the pontine nuclei of horseradish peroxidase labeled wheat germ agglutinin. Pontocerebellar axons were stained throughout their length and dense terminal label was present in the granular layer. The cerebellar nuclei, however, contained only a few scattered labeled fibers without a consistent distribution from case to case. If nuclear collaterals from pontocerebellar fibers exist, they appear to be very few and can be expected to give only a very small contribution to the excitatory input to the cerebellar nuclei.