Cerebellar language and cognitive functions in childhood: A comparative review of the clinical research

Background: Recent research addressing evidence from functional neuroimaging studies, neurophysiological research, and new advances in neuropsychology together with traditional cerebellar lesion studies have recently implicated the cerebellum in adult language and cognitive functions. However, more limited information is currently available in describing the functional connectivity present in the paediatric population. Aims: It is the purpose of this paper to review recent clinical research pertaining to paediatric populations, outlining the impact of site of lesion and specific associated clinical changes in children with cerebellar disturbances. Main contribution: The specific contribution of the right cerebellar hemisphere to language function is identified to also exist in the paediatric population, highlighting the existence of functional connections between this region of the brain and left frontal cortical areas early in development. Conclusions: Implications for future research in paediatric populations are extensive, as a greater awareness and an understanding of the recently acknowledged involvement of the cerebellum in cognition and nonmotor linguistic function is anticipated to also add new dimension and direction to the analysis of childhood language outcomes associated with the cerebellum.

A common oscillator for perceptual rivalries?

Perceptual rivalry is an oscillation of conscious experience that takes place despite univarying, if ambiguous, sensory input. Much current interest is focused on the controversy over the neural site of binocular rivalry, a variety of perceptual rivalry for which a number of different cortical regions have been implicated. Debate continues over the relative role of higher levels of processing compared with primary visual cortex and the suggestion that different forms of rivalry involve different cortical areas. Here we show that the temporal pattern of disappearance and reappearance in motion-induced blindness (MIB) (Bonneh et al, 2001 Nature 411 798-801) is highly correlated with the pattern of oscillation reported during binocular rivalry in the same individual. This correlation holds over a wide range of inter-individual variation. Temporal similarity in the two phenomena was strikingly confirmed by the effects of the hallucinogen LSD, which produced the same, extraordinary, pattern of increased rhythmicity in both kinds of perceptual oscillation. Furthermore, MIB demonstrates the two properties previously considered characteristic of binocular rivalry. Namely the distribution of dominance periods can be approximated by a gamma distribution and, in line with Levelt's second proposition of binocular rivalry, predominance of one perceptual phase can be increased through a reduction in the predominance time of the opposing phase. We conclude that (i) MIB is a form of perceptual rivalry, and (ii) there may be a common oscillator responsible for timing aspects of all forms of perceptual rivalry.

Spreading and synchronization of intrinsic signals in visual cortex of macaque monkey evoked by a localized visual stimulus

Spatio-temporal maps of the occipital cortex of macaque monkeys were analyzed using optical imaging of intrinsic signals. The images obtained during localized visual stimulation (IS) were compared with the images obtained on presentation of a blank screen (IB). We first investigated spontaneous variations of the intrinsic signals by analyzing the 100 IBs for each of the three cortical areas. Slow periodical activation was observed in alternation over the cortical areas. Cross-correlation analysis indicated that synchronization of spontaneous activation only took place within each cortical area, but not between them. When a small, drifting grating (2degreesX2degrees) was presented on the fovea. a dark spot appeared in the optical image at the cortical representation of this retinal location. It spread bilaterally along the border between V1 and V2, continuing as a number of parallel dark bands covering a large area of the lateral surface of V1. Cross-correlation analysis showed that during visual stimulation the intrinsic signals over all of the three cortical areas were synchronized, with in-phase activation of V1 and V2 and anti-phase activation of V4 and V1/V2. The significance of these extensive synergistic and antagonistic interactions between different cortical areas is discussed. (C) 2003 Elsevier B.V. All rights reserved.

Pyramidal cell specialization in the occipitotemporal cortex of the vervet monkey

Pyramidal cells were injected intracellularly in fixed, flat-mounted cortical slices taken from the first and fourth visual areas (VI and V4, respectively) and cytoarchitectonic areas TEO and TE of two age and gender-matched vervet monkeys and the size, branching complexity and spine density of their basal dendritic trees determined. In both animals, we found marked differences in the pyramidal cell phenotype between cortical areas. More specifically, a consistent trend for larger, more branched and more spinous pyramidal cells with progression through VI, V4, TEO and TE was observed. These findings support earlier reports of interareal specialization in pyramidal cell structure in occipitotemporal visual areas in the macaque monkey. (c) 2005 Lippincott Williams & Wilkins.

Pyramidal cell specialization in the occipitotemporal cortex of the Chacma baboon (Papio ursinus)

Pyramidal cell structure varies systematically in occipitotemporal visual areas in monkeys. The dendritic trees of pyramidal cells, on average, become larger, more branched and more spinous with progression from the primary visual area (V1) to the second visual area (V2), the fourth (V4, or dorsolateral DL visual area) and inferotemporal (IT) cortex. Presently available data reveal that the extent of this increase in complexity parallels the expansion of occipitotemporal cortex. Here we extend the basis for comparison by studying pyramidal cell structure in occipitotemporal cortical areas in the chacma baboon. We found a systematic increase in the size of and branching complexity in the basal dendritic trees, as well as a progressive increase in the spine density along the basal dendrites of layer III pyramidal cells through V1, V2 and V4. These data suggest that the trend for more complex pyramidal cells with anterior progression through occipitotemporal visual areas is not a feature restricted to monkeys and prosimians, but is a widespread feature of occipitotemporal cortex in primates.

Regional specialization in pyramidal cell structure in the limbic cortex of the vervet monkey (Cercopithecus pygerythrus): an intracellular injection study of the anterior and posterior cingulate gyrus

The pyramidal cell phenotype varies quite dramatically in structure among different cortical areas in the primate brain. Comparative studies in visual cortex, in particular, but also in sensorimotor and prefrontal cortex, reveal systematic trends for pyramidal cell specialization in functionally related cortical areas. Moreover, there are systematic differences in the extent of these trends between different primate species. Recently we demonstrated differences in pyramidal cell structure in the cingulate cortex of the macaque monkey; however, in the absence of other comparative data it remains unknown as to whether the neuronal phenotype differs in cingulate cortex between species. Here we extend the basis for comparison by studying the structure of the basal dendritic trees of layer III pyramidal cells in the posterior and anterior cingulate gyrus of the vervet monkey (Brodmann's areas 23 and 24, respectively). Cells were injected with Lucifer Yellow in flat-mounted cortical slices, and processed for a light-stable DAB reaction product. Size, branching pattern, and spine density of basal dendritic arbors were determined, and somal areas measured. As in the macaque monkey, we found that pyramidal cells in anterior cingulate gyrus (area 24) were more branched and more spinous than those in posterior cingulate gyrus (area 23). In addition, the extent of the difference in pyramidal cell structure between these two cortical regions was less in the vervet monkey than in the macaque monkey.

DISLEXIA E ATENÇÃO

Dislexia é uma condição neurológica associada a deficiências na aquisição e processamento da linguagem. Variando em graus de gravidade, que se manifesta por dificuldades na linguagem receptiva e expressiva, incluindo processamento fonológico, na leitura, escrita, ortografia, caligrafia, e por vezes em aritmética. Dislexia é uma condição hereditária associada a diversas anormalidades neurológicas em áreas corticais visuais e auditivas. Uma das mais influentes teorias para explicar os sintomas disléxicos é a chamada hipótese magnocelular. Segundo esta hipótese, a dislexia resulta de processamento de informações visuais anormais, devido principalmente a disfunção no sistema magnocelular. Esta dissertação explora esta hipótese comparando quinze indivíduos com dislexia e quinze controles, com idades compreendidas entre os 18 e os 30 anos através de dois testes visuais de atenção. Ambos os experimentos avaliam tempo de reação a estímulos que apareciam em toda tela do computador, enquanto os indivíduos permaneciam instalados, com a cabeça apoiada por um chin rest e com os olhos fixos em um alvo central. O experimento I consistiu de estímulos (pequenos círculos) brancos apresentados em um fundo preto. No experimento II, a mesma metodologia foi utilizada, mas agora com os estímulos (pequenos círculos) verdes sobre um fundo vermelho. Os resultados foram analisados levando em consideração os quadrantes onde os estímulos foram apresentados. Pacientes e controles não diferiram em relação ao tempo de reação a estímulos apresentados no campo visual inferior, em comparação ao quadrante superior de um mesmo indivíduo. Considerando todos os quadrantes, disléxicos tiveram tempo de reação mais lento no experimento I, mas apresentaram tempos de reação semelhantes aos controles no experimento II. Estes resultados são compatíveis com anormalidades no sistema magnocelular. As implicações destes achados para a fisiopatologia da dislexia, bem como para o seu tratamento devem ser mais discutidos.(AU)

Quantification of the pathological changes with laminar depth in the cortex in sporadic Creutzfeldt-Jakob disease

The laminar distribution of the vacuolation ('spongiform change'), surviving neurons, glial cell nuclei, and prion protein (PrP) deposits was studied in the frontal, parietal and temporal cortex in 11 cases of sporadic Creutzfeldt-Jakob disease (CJD). The distribution of the vacuolation was mainly bimodal with peaks of density in the upper and lower cortical laminae. The density of surviving neurons was greatest in the upper cortex while glial cell nuclei were distributed largely in the lower cortex. PrP deposits exhibited either a bimodal distribution or reached a maximum density in the lower cortex. The vertical density of the vacuoles was positively correlated with the surviving neurons in 12/44 of cortical areas studied, with glial cell nuclei in 16/44 areas and with PrP deposition in 15/28 areas. PrP deposits were positively correlated with glial cell nuclei in 12/31 areas. These results suggest that in sporadic CJD: (1) the lower cortical laminae are the most affected by the pathological changes; (2) the development of the vacuolation may precede that of the extracellular PrP deposits and the glial cell reaction; and (3) the pathological changes may develop initially in the lower cortical laminae and spread to affect the upper cortical laminae. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

Spatial correlations between the vacuolation, prion protein deposits, and surviving neurons in the cerebral cortex in sporadic Creutzfeldt-Jakob disease

In the cerebral cortex of cases of sporadic Creutzfeldt-Jakob disease (sCJD), the vacuolation (spongiform change) and PrP deposits are aggregated into clusters which are regularly distributed parallel to the pia mater. The objective of the present study was to determine the spatial relationships between the clusters of the vacuoles and PrP deposits and between the pathological changes and variations in the density of surviving neurons. In areas with low densities of pathological change, clusters of vacuoles were spatially correlated with the surviving neurons and not with the PrP deposits. By contrast, in more significantly affected areas, clusters of vacuoles were spatially correlated with those of the PrP deposits and not with the surviving neurons. In addition, areas with a high density of vacuoles and a low density of PrP deposits exhibited no spatial correlations between the variables. These data suggest that the spatial relationships between the vacuolation, PrP deposits and surviving neurons in sCJD depend on the density of lesions present. Differences in the pattern of correlation may reflect the developmental stage of the pathology in particular cortical areas.

The spatial patterns of pathological brain lesions in 12 patients with corticobasal degeneration

Corticobasal degeneration (CBD) is a rare and progressive neurological disorder characterised by the presence of ballooned neurons (BN) and tau positive inclusions in neurons and glial cells. We studied the spatial patterns of the BN, tau positive neurons with inclusions (tau + neurons), and tau positive plaques in the neocortex and hippocampus in 12 cases of CBD. All lesions were aggregated into clusters and in many brain areas, the clusters were distributed in a regular pattern parallel to the tissue boundary. In the majority of cortical areas, the clusters of BN were larger in the lower compared with the upper laminae while the clusters of tau + neurons were larger in the upper laminae. Clusters of BN and tau + neurons were either negatively correlated or not significantly correlated in the upper and lower cortical laminae. Hence, BN and tau + lesions in CBD exhibit similar spatial patterns as lesions in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Pick's disease (PD). The location, sizes and distribution of the clusters in the neocortex suggest that the tau + lesions may be associated with the degeneration of the feedforward and the BN the feedback cortico-cortical and/or the efferent cortical pathways. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

A quantitative study of the pathological changes in white matter in multiple system atrophy

The density and spatial distribution of the vacuoles, glial cell nuclei and glial cytoplasmic inclusions (GCI) were studied in the white matter of various cortical and subcortical areas in 10 cases of multiple system atrophy (MSA). Vacuolation was more prevalent in subcortical than cortical areas and especially in the central tegmental tract. Glial cell nuclei widespread in all areas of the white matter studied; overall densities of glial cell nuclei being significantly greater in the central tegmental tract and frontal cortex compared with areas of the pons. The GCI were present most consistently in the external and internal capsules, the central tegmental tract and the white matter of the cerebellar cortex. The density of the vacuoles was greater in the MSA brains than in the control brains but glial cell density was similar in both groups. In the majority of areas, the pathological changes were distributed across the white matter randomly, uniformly, or in large diffuse clusters. In most areas, there were no spatial correlations between the vacuoles, glial cell nuclei and GCI. These results suggest: (i) there is significant degeneration of the white matter in MSA characterized by vacuolation and GCI; (ii) the central tegmental tract is affected significantly more than the cortical tracts; (iii) pathological changes are diffusely rather than topographically distributed across the white matter; and (iv) the development of the vacuoles and GCI appear to be unrelated phenomena. © 2007 Japanese Society of Neuropathology.

Topography of α-internexin-positive neuronal aggregates in 10 patients with neuronal intermediate filament inclusion disease

Abnormal neuronal intermediate filament (IF) inclusions immunopositive for the type IV IF α-internexin have been identified as the pathological hallmark of neuronal intermediate filament inclusion disease (NIFID). We studied the topography of these inclusions in the frontal and temporal lobe in 68 areas from 10 cases of NIFID. In the cerebral cortex, CA sectors of the hippocampus, and dentate gyrus granule cell layer, the inclusions were distributed mainly in regularly distributed clusters, 50-800 μm in diameter. In seven cortical areas, there was a more complex pattern in which the clusters of inclusions were aggregated into larger superclusters. In 11 cortical areas, the size of the clusters approximated to those of the cells of origin of the cortico-cortical pathways but in the majority of the remaining areas, cluster size was smaller than 400 μm. The topography of the lesions suggests that there is degeneration of the cortico-cortical projections in NIFID with the formation of α-internexin-positive aggregates within vertical columns of cells. Initially, only a subset of cells within a vertical column develops inclusions but as the disease progresses, the whole of the column becomes affected. The corticostriate projection appears to have little effect on the cortical topography of the inclusions. © 2006 EFNS.

Spatial correlations between the vacuolation, prion protein deposition and surviving neurons in variant Creutzfeldt-Jakob Disease (vCJD)

The histological features of cases of variant Creutzfeldt-Jakob disease (vCJD) are often distributed in the brain in clusters. This study investigated the spatial associations between the clusters of the vacuoles, surviving neurons, and prion protein (PrP) deposits in various brain areas in 11 cases of vCJD. Clusters of vacuoles and surviving neurons were positively correlated in the cerebral cortex but negatively correlated in the dentate gyrus. Clusters of the florid and diffuse type of PrP deposit were not positively correlated with those of either the vacuoles or the surviving neurons although a negative correlation was observed between the florid plaques and surviving neurons in some cortical areas. Clusters of the florid and diffuse deposits were either negatively correlated or uncorrelated. These data suggest: 1) that clusters of vacuoles in the cerebral cortex are associated with the presence of surviving neuronal cell bodies, 2) that the clusters of vacuoles are not spatially related to those of the PrP deposits, and 3) different factors are involved in the pathogenesis of the florid and diffuse PrP deposits.

Clustering of neuronal inclusions in "dementia with neurofilament inclusions"

Dementia with neurofilament inclusions (DNI) is a new disorder characterized clinically by early-onset dementia and histologically by the presence of intraneural inclusions immunopositive for neurofilament antigens but lacking tau and α-synuclein reactivity. We studied the clustering patterns of the neurofilament inclusions (NI) in regions of the temporal lobe in three cases of DNI to determine whether they have the same spatial patterns as inclusions in the tauopathies and α-synucleinopathies. The NI exhibited a clustered distribution (mean size of clusters 400 μm, range 50-800 μm, SD 687.8) in 24/28 of the areas studied. In 22 of these areas, the clusters exhibited a regular distribution along the tissue parallel to the pia mater or alveus. In 3 cortical areas, there was evidence of a more complex pattern in which the NI clusters were aggregated into larger superclusters. In 6 cortical areas, the size of the clusters approximated to those of the cells of origin of the cortico-cortical pathways but in the remaining areas cluster size was smaller than 400 μm. Despite the unique molecular profile of the NI, their spatial patterns are similar to those shown by filamentous neuronal inclusions in the tauopathies and α-synucleinopathies.

Quantification of the vacuolation (spongiform change) and prion protein deposition in 11 patients with sporadic Creutzfeldt-Jakob disease

The vacuolation (spongiform change) and prion protein (PrP) deposition were quantified in the cerebral cortex, hippocampus and cerebellum of 11 patients with sporadic Creutzfeldt-Jakob disease (CJD). The density of the vacuolation, averaged over patients, was greatest in the occipital cortex and cerebellum and least in the dentate gyrus. The degree of PrP deposition was similar in the different cortical areas and in the cerebellum but significantly lower in the hippocampus and absent in the dentate gyrus. There were no significant differences in the extent of the vacuolation and PrP deposition in the upper and lower cortical laminae. Vacuolation and PrP deposition in the upper cortex were both positively correlated with corresponding levels in the lower cortex. In addition, in the parietal cortex and parahippocampal gyrus, the density of the vacuolation was positively correlated with the level of PrP deposition but no such correlations were observed in the remaining areas studied. This quantitative study suggested that: (1) the pathological changes were most severe in the occipital cortex and cerebellum, while the hippocampus was least affected, (2) the pathological changes affect the upper and lower cortical laminae, and (3) the degree of correlation between the density of the vacuolation and PrP deposition may be dependent on brain region.