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Biomedical subjects

F M Benes

Publications and source records attributed to F M Benes.

At least 73 records · Page 4Linked to original sources

Myelination of cortical-hippocampal relays during late adolescence.

The normal developmental series of brains in the Yakovlev Collection has been examined to explore the possibility that various brain regions implicated in schizophrenia may show changes in myelination during late adolescence, a period coinciding with the appearance of early symptoms of this disorder. The prefrontal, cingulate, and parahippocampal (entorhinal) cortex, as well as the perforant pathway, cingulum bundle, and hippocampus, were closely examined because these regions have recently been found to show various neuropathological differences in schizophrenia. Observation of these specimens has confirmed earlier reports by Yakovlev and Lecours (1967) that primary motor and sensory cortices show robust myelination early in the first decade of life. In contrast, associative cortical areas show increased amounts of myelin staining only by the second decade, although some cortical areas, like the cingulate and basofrontal cortex, remain poorly myelinated throughout life. The most striking finding, however, was the appearance of increased myelination of the subicular and presubicular regions during the late adolescent period. Increased myelination in the subiculum was localized to a discrete region at the surface where fibers of the perforant pathway are known to aggregate as they course toward the area dentata. The comparable region in the adjacent presubicular area that also showed increased myelin staining probably contains distal portions of the cingulum bundle. Support for this latter possibility was obtained from a single case in which a stereotaxically placed lesion causing interruption of the cingulum bundle showed less myelin in the presubicular area of the effectively lesioned side.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

High resolution imaging of receptor binding in analyzing neuropsychiatric diseases.

A method for analyzing high resolution imaging of receptor binding activity in human post-mortem brain specimens is described. The autoradiography technique employed is based on methods previously described by others in which coverslips dipped in tritium-sensitive nuclear track emulsion are placed over a tissue section that has been incubated in a medium containing radioactively-tagged ligand. With this approach, there is a 370-fold increase in resolution from approximately 120 microns available with tritium-sensitive films to 0.33 micron attainable with the emulsion approach. Since the coverslip autoradiogram remains superimposed on the tissue section, individual grains can be routinely quantitated in specific cell types and discrete subregions of the neuropil with the aid of a user-interactive image processing system. Overall, the improved resolution that this approach provides makes it possible to determine whether a particular neuronal sub-type may be preferentially altered by disease processes affecting the brain.

Autoradiography↗

Laminar-specific distribution and infrastructural detail of amyloid in the Alzheimer disease cortex visualized by computer-enhanced imaging of epitopes recognized by monoclonal antibodies.

Monoclonal antibodies to the A4 amyloid polypeptide were used in immunocytochemical staining of the Alzheimer disease prefrontal cortex. Analysis of the resulting staining patterns allowed us to evaluate the amounts and distribution of amyloid-protein deposits exclusive of other senile-plaque components. Previously unappreciated infra-structural details of amyloid in the Alzheimer disease brain became accessible through computer-enhanced imaging procedures. Four discrete morphologic classes of amyloid deposits were observed and classified as punctate, macular, ring, and ring-with-core configurations. Computer imaging indicated that all four classes of immunostained deposits contain internal gradients of density. The classes were nonuniformly distributed with regard to size and location within cortical laminae. Our results support two separate but complementary hypotheses concerning the molecular neuropathology of Alzheimer disease in the prefrontal cortex. (i) Irrespective of cortical layer or morphology, density-gradient analyses suggest that amyloid deposits are elaborated through molecular and cellular events that may involve diffusion or coalescence of the A4 polypeptide. (ii) The distribution and morphology of prefrontal cortical amyloid deposits may be dependent upon underlying laminar-specific structures of the neocortex.

Alzheimer Disease↗

Comparison of MRI and CT scans in a group of psychiatric patients.

The authors compared the results of computerized tomography (CT) and magnetic resonance imaging (MRI) scans of 16 psychotic patients with various diagnoses whose neurologic examinations suggested structural brain abnormalities. Blind readings showed a high concordance of findings, including ventricle-to-brain ratios, although MRI appeared superior in visualizing midline structures and identifying atrophic changes. Because it requires no ionizing radiation, MRI allows multiple studies of the same patient, study of family members, and recruitment of unbiased samples of control subjects. Use of MRI may help address questions regarding the specificity and prevalence of brain abnormalities observed with CT in psychotic patients.

Adolescent↗

A modular arrangement of neuronal processes in human cortex: disruption with aging and in Alzheimer's disease.

Studies were undertaken to assess whether or not neuron-specific immunostaining of the human brain can reveal unique cytoarchitectural features that may be affected by healthy aging and Alzheimer's disease (AD). Human prefrontal cortex (PFC) and anterior cingulate cortex (ACC) were stained with an antibody raised against the neurofilament protein 200,000 molecular weight subunit (NFP-200) using an avidin-biotin immunolocalization procedure. Immunostaining of cortex was neuron-specific and highlighted axons in particular. This staining has revealed an orderly arrangement of horizontal and vertical axon bundles which form latticelike compartments or modules throughout most of the matrix of the two cortical areas studied. The ACC shows this pattern to be intact in individuals through the ninth decade, while the PFC there was blurring of the modularity beyond the fifth decade. Irrespective of the age-related blurring of the latticelike arrangement of axons in PFC, neurologically normal elderly individuals nevertheless showed a highly organized appearance to the cortical matrix. By contrast, patients with AD showed a marked disruption of the modular arrangement of fibers in PFC, but not ACC. Differences between PFC fibers in controls and AD patients were also demonstrated with an axon-specific monoclonal antibody that reacted with phosphorylated epitopes of the NFP-200. The chaotic appearance of fiber staining in PFC seen in patients with AD was noted to be present in one subject who died in an early stage of the disease. The possible significance of this previously unknown aspect of cortical cytoarchitecture for normal cognitive functioning in humans is discussed.

Adolescent↗

Post-mortem structural analyses of schizophrenic brain: study designs and the interpretation of data.

This paper discusses various factors that must be considered in designing histological studies of schizophrenic brain. An examination of the literature prior to 1952 reveals that much of the controversy arising during the first half of this century can be understood within the context of methodological flaws that included the use of inappropriate controls, the lack of systematic diagnosis of schizophrenia, an absence of blind quantitation and finally, a failure to control for the effects of several potential confounding variables. In addition to these latter concerns, the design of post-mortem structural analyses of schizophrenic brain must also consider what brain areas are reasonable to examine, what morphometric parameters should be evaluated to test a hypothesis in question and whether any differences noted represent primary, secondary or perhaps even epiphenomenal changes in the brain. The life cycle of schizophrenic patients should be considered in these designs so that factors intrinsic to the disorder, such as a genetic trait marker or the effects of perinatal insult, can be distinguished from changes that may arise later, perhaps in relation to the acquisition of the defect state. The basic principles of neurobiology and clinical psychiatry should be applied in developing a design and in interpreting data that emerges. Taking all of these issues into account, complex strategies will be required in order to obtain reliable, valid and clinically relevant information that can contribute to our understanding of the pathophysiology of schizophrenia.

Age Factors↗

An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients.

A series of computer-assisted stereomorphometric analyses of the spatial arrangements of neurons and glia in postmortem cerebral cortex specimens has been developed and applied to both control subjects and schizophrenic patients. The data suggest that the anterior cingulate cortex of schizophrenic patients may contain domains or aggregates of neurons, particularly in layer II, which are smaller in size and separated by wider distances than those observed in the control group. Verification of the inferences made from the computer-generated data has been obtained by direct microscopic visualization and measurement of neuronal aggregates of layer II in Nissl-stained cingulate specimens from the control and schizophrenic groups. Statistical correction of the data, using multivariate statistics, for effects of age, hypoxia, postmortem interval, fixation, and neuroleptic exposure does not eliminate the differences in size and separation of neuronal aggregates in layer II of schizophrenic patients. The possible relevance of these findings to our understanding of schizophrenic symptomatology is discussed.

Aged↗

Increased vertical axon numbers in cingulate cortex of schizophrenics.

Data generated from an earlier study have suggested a model in which greater numbers of long, vertical, associative axons may occur in the anterior cingulate cortex of schizophrenic patients relative to control subjects. This hypothesis has now been tested using neuron-specific antibodies raised against the 200-kilodalton neurofilament subunit, a component of neuronal cytoskeleton, to immunostain axons of human postmortem cingulate cortex. A manual method for counting axons in the region of layer II and sublamina IIIA has been designed and applied blindly to parallel control and schizophrenic immunoprocessed specimens. The results show that there are 25% more vertical axons in the schizophrenic than in the control specimens. Preferentially higher numbers of both long vertical axons (62%) and axons associated with blood vessels (52%) have also been noted in the schizophrenic specimens. By contrast, the number of large-caliber horizontal axons was the same in the two groups; therefore, the greater number of vertical axons in schizophrenic specimens does not appear to represent a nonspecific effect. When these data are corrected for the effects of several confounding variables using analysis of covariance, the overall pattern of the results persists. These findings suggest the possibility that there might be an increase of associative inputs into the anterior cingulate cortex of schizophrenic patients, although it is not clear at present whether the differences noted, if replicative, may be primarily or perhaps only secondarily related to the disorder.

Axons↗

The spatial distribution of neurons and glia in human cortex based on the poisson distribution.

A method was devised that employs deviations from the Poisson distribution to analyze the spatial arrangement of neurons and glia in human cerebral cortex. A field of randomly distributed points equal in number of a sample field of neuronal or glial cells is generated by computer, and the proportion of cells in the sample field that are closer to the nearest neighboring cells than to the nearest randomly distributed point is determined. We call this proportion the "Poisson ratio." When the cells are randomly distributed, the Poisson ratio is equal to 0.5. If the Poisson ratio is less than 0.5, the cells are farther away from one another than a random distribution would predict (exclusionary pattern); if the Poisson ratio is greater than 0.5, the cells are closer to one another than a random distribution would predict (clustering). A simple nonparametric statistical test is used to determine the significance of differences in the ratios. This method was applied to samples of human cerebral cortex in order to test the hypothesis that patients with schizophrenic psychosis may have an altered pattern of neuronal clustering. The analysis revealed that there is no difference in the nearest-neighbor distribution of either neurons or glia between psychotic patients and controls. It was found, however, that there is a highly significant difference in the spatial distribution of neurons versus glia in human cerebral cortex. Neurons of layers II to VI in the human cortex show greater-than-expected distances among them and are distributed according to an exclusionary pattern, while neurons in layer I show a clustering pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral Cortex↗

Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics.

Quantitative morphometric determinations of neuronal and glial density, neuron-glia ratios, and neuronal size were performed in the prefrontal, anterior cingulate, and primary motor cortex of ten controls and ten schizophrenics diagnosed by Feighner criteria under blind conditions to assess whether neuronal degeneration had occurred. Stepwise multiple regression and multiple classification analyses were used to evaluate the effect of potential confounding variables such as age, postmortem interval, fixation, hypoxia, and neuroleptic exposure on the measures studied. The neuronal density was significantly lower in layer VI of the prefrontal, layer V of the cingulate, and layer III of motor cortex. There was also a trend toward fewer neurons in most layers of both prefrontal and motor cortex, although by discriminant analysis this generalized pattern was significant only for the prefrontal area. The glial density also tended to be lower throughout most layers of all three cortical regions. There were no differences in the neuron-glia ratios or neuronal size between the two groups. The data do not support the presence of neuronal degeneration in schizophrenic cortex as it is conventionally described by neuropathologists, but do suggest the possibility that cytoarchitectural variations in cortical structure might exist in this group of schizophrenics.

Aged↗

Synaptic rearrangements in medial prefrontal cortex of haloperidol-treated rats.

The effects of daily administration of haloperidol for 16 weeks on the structure of layer VI in medial prefrontal cortex of rat was performed at the light and electron microscopic levels. At the light microscopic level, no difference in either the size or the density of neurons was observed. At the electron microscopic level, the mean dendritic calibre of haloperidol-treated rats was twice that observed in control animals, but this was due to a selective loss of small-calibre dendritic profiles. Rats treated with neuroleptic also showed a reduction in axon terminals with asymmetric postsynaptic membrane specializations, which, in control animals, were preferentially associated with small-calibre dendritic profiles. These small-calibre dendritic profiles were found to be spines rather than small terminal dendritic shafts. An increase in axon terminals showing no membrane specialization on larger dendritic profiles also occurred in rats treated daily with the neuroleptic. The data suggest the possibility that haloperidol may have induced a relocation of asymmetric terminals from resorbed spinous processes to larger dendritic branches with the concomitant loss of their postsynaptic membrane specialization.

Animals↗

The effects of haloperidol on synaptic patterns in the rat striatum.

A morphometric analysis of the corpus striatum of rats chronically treated with haloperidol was performed at the light and electron microscopic levels. Although the density of striatal neurons was unchanged in the haloperidol-treated group, there was a small increase in neuronal size (13%). This change in cell size was paralleled by a trend towards larger dendrite calibres occurring in the drug-treated animals. The distribution curve for axon terminal size indicated that 12% of the overall population was shifted from a range with a median size of 0.8 micron 2 to one with 1.6 micron 2 in the drug-treated group. This increase in size of some striatal terminals was accompanied by a concomitant increase in numbers of their associated synaptic vesicles, resulting in a similar density of vesicles for both control and drug-treated animals.

Animals↗

Behavioral correlates of computed tomographic (CT) scan changes in older psychiatric patients.

Fifty psychiatric inpatients aged 50 and over, with no hard neurologic findings, and with a variety of DSM-III diagnoses (adjustment disorder, affective illness, and dementia), were rated for behavioral and psychiatric symptoms using the Geriatric Rating Scale and the Nurse's Assessment of Global Symptomatology-Elderly. These clinical ratings were correlated with computed tomographic (CT) scan assessments of various superficial cerebral regions as well as with linear measures of ventricular size. Behavioral deficits in activities of daily living (ADL) plus an interactional variable, inability to respond to requests, were correlated with superior temporal and inferior parietal CT abnormalities, particularly on the left side. Suspiciousness and peculiar thinking, mood lability and irritability, as well as impaired memory with confusion, perplexity, and disorientation were also associated with atrophy in these same regions. Prefrontal area defects correlated with mood lability and deficits in visual-interactional responsiveness. Statistically controlling for effects of age and alcohol abuse did not alter the basic nature of these results. Regional cerebral specialization in relation to these results are discussed using concepts developed by Luria.

Activities of Daily Living↗

Immunostaining of neurofilament protein in human postmortem cortex: a sensitive and specific approach to the pattern analysis of human cortical cytoarchitecture.

Antibodies raised against the 200 000 neurofilament protein (NFP) of rat brain have been successfully applied to the staining of human postmortem cortex using a modified immunoperoxidase procedure. Human anterior cingulate cortex which has been in formaldehyde fixative for as long as 4 years shows extensive and reliable staining of axons and, to a lesser degree, apical dendrites of cortical neurons. The immunostaining of 200 000 NFP in human cortex has revealed cytoarchitectural details not generally visible with other more conventional neuroanatomical stains, particularly when counterstaining with cresyl violet is employed. Potential applications of this approach to the pattern analysis of human cortical cytoarchitecture in both health and disease are discussed.

Animals↗

Haloperidol-induced plasticity of axon terminals in rat substantia nigra.

An electron micrographic morphometric analysis of nerve endings in substantia nigra of rats repeatedly treated with haloperidol was performed. Although most parameters showed no difference, drug-treated animals exhibited a significant shift in the distribution of relative numbers of axon terminals, suggesting neuroleptic-induced axon-collateral sprouting.

Animals↗

CT scan studies of superficial cerebral regions: frequency and distribution of abnormalities in elderly psychiatric patients.

The CT scans of 50 elderly psychiatric patients were evaluated for the presence of discrete cerebral abnormalities. The prefrontal, superior temporal and inferior parietal areas showed the most frequent occurrence of defects. Motor, sensory and tertiary visual cortical regions, on the other hand, did not commonly exhibit signs of atrophy or sulcal widening. Clinical diagnoses of depression and dementia occurred in patients whether or not specific gyral defects were present, and therefore did not predict their presence. Patients with regional cerebral defects, however, were more likely to be older and to have sustained severe neurological insults. Patients with affective disorders who were treated with ECT showed no differences in the occurrence of superficial cerebral defects.

Aged↗

Biochemical and morphometric studies of the relationship of acetylcholine synthesis and vesicle numbers after stimulation of frog neuromuscular junctions: the effect of a choline-O-acetyltransferase inhibitor.

The present study compares choline acetylase (ChAc) activity with morphometric determinations of synaptic vesicles at the neuromuscular junctions of frog pectoralis muscle subjected to high and low frequency stimulation in the presence or absence of NVP, a ChAc inhibitor. Muscles stimulated at 10/sec for 20 min with one hour rest, in the presence of NVP, showed an approximately 50% reduction in synthesis of Ach, and a 50--60% reduction in the numerical density of synaptic vesicles relative to controls preparations. Similar nerve muscle preparations stimulated at 2/sec for one hour without rest, in the presence of NVP, also showed approximately 50% less synthesis of Ach and vesicle numbers 43% lower than that seen in control muscles treated in the same way in the absence of drug. The results indicate a correlation between the inhibitory effect of NVP on ChAc and the numbers of vesicles present within terminals. In addition, stimulation of nerve terminals, with or without NVP, produced a significant increase in the numerical density of synaptic vesicles over respective unstimulated controls. These and other results are discussed in relation to current hypotheses concerning recirculation of synaptic vesicles.

Acetylcholine↗

Rapid dendritic atrophy following deafferentation: an EM morphometric analysis.

The nucleus laminaris (NL), a third-order brain stem auditory nucleus in birds, receives afferents to its dorsal dendrites from the ipsilateral nucleus magnocellularis (NM), while the ventral dendrites of NL neurons are innervated by axons from the contralateral NM via the crossed dorsal cochlear tract (CTrX). The CTrx was transected in young chickens and, 96 h later, NL was examined for cytological changes. A morphometric analysis of electron micrographs from lesioned and shamd axon terminals were localized almost entirely to the ventral neuropil region of NL. (2) The volume density of dendrite in the ventral region of NL of lesioned animals was reduced by 85% compared to both the dorsal dendritic region of the same animals and the ventral dendritic region of sham-operated control animals. (3) The frequency with which primary dendrites were encountered in the ventral neuropil of lesioned animals was 81% lower than sham-operated controls. (4) Frequently, there was an apparent reduction in the amount of rough endoplasmic reticulum, Golgi apparatus and cytoplasmic granularity in the deafferented part of the NL neurons. (5) The data indicate that the cytological integrity of dendritic processes cna be specifically, profoundly and very rapidly compromised by removing a significant proportion of their afferents, suggesting that a tonic influence may be exerted by the presynaptic terminals.

Animals↗