Model Of Human Brain Research Articles

Altered Gene Expression Profiles Reveal Similarities and Differences Between Parkinson Disease and Model Systems

Parkinson disease (PD) targets dopaminergic neurons in the substantia nigra, resulting in motor disturbances such as resting tremor, bradykinesia, and rigidity. Pathogenic processes likely occur over several decades, in that an overwhelming percentage of neurons are already dead at the time of clinical diagnosis. For this reason, the usage of animal model systems to discover the early steps in the pathologic cascade is required. These include exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which selectively kills dopamine neurons in the substantia nigra, and genetic models incorporating mutations in the α-synuclein gene that cause disease in human patients. Through the evaluation of these models at multiple time points, it is possible to discover novel gene expression changes that may underlie disease pathogenesis. Specifically, the authors hypothesize that animal models of PD and human PD brains share a gene expression profile that signifies certain aspects of pathogenesis and/or recovery-resistance. To test this and similar hypotheses, the authors and others have utilized new microarray technology that enables the sampling of thousands of genes’ expression level in one assay. Because the technology is fairly new and results can vary depending on methods used, results must be evaluated with care. Multiple array and data-mining options can be used to make the most accurate inferences as to differentially expressed genes in each set of samples. The authors developed a fusion classifier approach whereby individual data-mining algorithms generate lists of significant genes. The lists are subsequently queried, and only genes unanimously called significant are retained for further validation. Although the authors’ approach identified hundreds of differentially expressed genes in each of three PD systems, only a few were common between the human and animal substantia nigra. These were related to dopamine phenotype, synaptic function, and the mitochondrial metabolism, implicating the presynaptic terminal as a primary site of injury. The time course of the authors’ experiments indicates that if the synaptic changes could be prevented, this may alleviate some cell death, in that these changes precede neuronal loss.

Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease

Three mouse models of Alzheimer's disease (AD) were used to assess changes in gene expression potentially critical to amyloid β-peptide (Aβ)-induced neuronal dysfunction. One mouse model harbored homozygous familial AD (FAD) knock-in mutations in both, amyloid precursor protein (APP) and presenilin 1 (PS-1) genes (APP NLh/NLh/PS-1 P264L/P264L), the other two models harbored APP over-expression of FAD mutations (Tg2576) with the PS-1 knock-in mutation at either one or two alleles. These mouse models of AD had varying levels of Aβ40 and Aβ42 and different latencies and rates of Aβ deposition in brain. To assess changes in gene expression associated with Aβ accumulation, the Affymetrix murine genome array U74A was used to survey gene expression in the cortex of these three models both prior to and following Aβ deposition. Altered genes were identified by comparing the AD models with age-matched control littermates. Thirty-four gene changes were identified in common among the three models in mice with Aβ deposition. Among the up-regulated genes, three major classes were identified that encoded for proteins involved in immune responses, carbohydrate metabolism, and proteolysis. Down-regulated genes of note included pituitary adenylate cyclase-activating peptide (PACAP), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor I receptor (IGF-IR). In young mice without detectable Aβ deposition, there were no regulated genes common among the three models, although 40 genes were similarly altered between the two Tg2576 models with the PS-1 FAD knock-in. Finally, changes in gene expression among the three mouse models of AD were compared with those reported in human AD samples. Sixty-nine up-regulated and 147 down-regulated genes were found in common with human AD brain. These comparisons across different genetic mouse models of AD and human AD brain provide greater support for the involvement of identified gene expression changes in the neuronal dysfunction and cognitive deficits accompanying amyloid deposition in mammalian brain.

Altered expression of hypothetical proteins in hippocampus of transgenic mice overexpressing human Cu/Zn-superoxide dismutase 1

BackgroundCu/Zn-superoxide dismutase 1 (SOD1), encoded on chromosome 21, is a key enzyme in the metabolism of reactive oxygen species (ROS) and pathogenetically relevant for several disease states including Down syndrome (DS; trisomy 21). Systematically studying protein expression in human brain and animal models of DS we decided to carry out "protein hunting" for hypothetical proteins, i.e. proteins that have been predicted based upon nucleic sequences only, in a transgenic mouse model overexpressing human SOD1.ResultsWe applied a proteomics approach using two-dimensional electrophoresis (2-DE) with in-gel digestion of spots followed by mass spectrometric (matrix-assisted laser desorption/ionization-time of flight) identification and quantification of hypothetical proteins using specific software. Hippocampi of wild type, hemizygous and homozygous SOD1 transgenic mice (SOD1-TGs) were analysed.We identified fourteen hypothetical proteins in mouse hippocampus. Of these, expression levels of 2610008O03Rik protein (Q9D0K2) and 4632432E04Rik protein (Q9D358) were significantly decreased (P < 0.05 and 0.001) and hypothetical protein (Q99KP6) was significantly increased (P < 0.05) in hippocampus of SOD1-TGs as compared with non-transgenic mice.ConclusionsThe biological meaning of aberrant expression of these proteins may be impairment of metabolism, signaling and transcription machinery in SOD1-TGs brain that in turn may help to explain deterioration of these systems in DS brain.

The cooling effect of liquid flow on the focussed ultrasound-induced heating in a simulated foetal brain.

There is a need to investigate the thermal effects of diagnostic ultrasound (US) to assist the development of appropriate safety guidelines for obstetric use. The cooling effect of a single liquid flow channel was measured in a model of human foetal brain and skull bone heated by a focussed beam of simulated pulsed spectral Doppler US. Insonation conditions were 5.7 micros pulses, repeated at 8 kHz from a focussed transducer operating with a centre frequency of 3.5 MHz, producing a beam of -6 dB diameter of 3.1 mm at the focus and power outputs of up to 255 +/- 5 mW. Brain perfusion was simulated by allowing distilled water to flow at various rates in a 2 mm diameter wall-less channel in the brain soft tissue phantom material. This study established that the cooling effect of the flowing water; 1. was independent of the acoustic source power, 2. was more effective close to the flow channel, for example, there was a marked cooling at a distance of 1 mm and negligible cooling at a distance of 3 mm from the channel; and 3. initially increased at low flow rates, but further increase above normal perfusion had very little effect.

Training of neural networks with search behaviour

The development of the physics of living systems is caused by the necessity of considering the specific features of their adaptive search behavior. This is one of the main properties of living systems distinguishing adaptable living systems from mechanisms and cybernetic robots. An efficient method for studying the adaptive properties of living systems is the construction and investigation of neural network models of human and animal brains ensuring highly efficient behavior under complex dynamic environmental conditions. In [1] we have already suggested the mathematical formalism for a description of self-adapting neural networks and their training that can be used to model the self-organization processes in open living systems. In the present paper, new neural network algorithms of this class are suggested. New capabilities of these algorithms inaccessible for the conventional supervisory algorithms of neural network training are examined.

Catecholamine metabolism in the brain by membrane-bound and soluble catechol-o-methyltransferase (COMT) estimated by enzyme kinetic values

A kinetic model was constructed to reevaluate the catecholamine metabolism in hypothetical brain homogenates. Earlier published kinetic values of recombinant membrane-bound (MB-) COMT and soluble (S-) COMT were combined with data suggesting that MB-COMT represents 70% and 30% of total COMT protein in human and rat brain, respectively. In the rat brain model L-DOPA and 3,4-dihydroxybenzoic acid were O-methylated mainly via S-COMT, while dopamine and noradrenaline, at low concentrations, were O-methylated slightly more by MB-COMT. In the human brain model dopamine and noradrenaline were metabolized primarily by MB-COMT. The ratio of meta (3-methoxy) over para (4-methoxy) product formation from 3,4-dihydroxybenzoic acid was higher for MB-COMT than S-COMT. It is suggested that MB-COMT clearly predominates the O-methylation of dopamine and noradrenaline also in vivo. Additionally, meta/para ratios could support the enrichment of either isoform of COMT in a homogenate sample.

GABA and L-glutamic acid release in en bloc resection slices of human hippocampus: an in vitro microdialysis study.

The interaction of neurotransmitters has been a major interest in pathophysiological conditions like epilepsy. In vivo microdialysis has recently gained much validity in measuring neurotransmitter release in experimental animals. However, there is a paucity of data concerning its use in humans on the grounds of safety considerations. Microdialysis experiments were performed using the hippocampal head region removed from patients with medically intractable seizures, who underwent surgery for mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Following en bloc resection, the tissues were immediately transferred to the essential in vitro milieu. Slices were incubated in lactated Ringer's solution and microdialysis probes inserted into the slices were perfused with artificial cerebrospinal fluid (aCSF). When the K+ concentration of aCSF was elevated to 100 mM, GABA and L-glutamic acid levels increased by 293% and 177%, respectively. This method may serve as an experimental model for human brain, to throw more light on the interactions between GABA and L-glutamic acid in hippocampal tissues obtained from patients with MTLE-HS.

Intelligent Control System Based on Human Information Processing

Researcher about the human brain modeling has possible new design of control systems for complex processes. This paper presents a structural/functional analysis of an intelligent autonomous system based on human intelligent control system. Human information processing is a most complex process that integrates all structure of human brain. An information processing model assumes that cognition can be analyzed into aseries of stage, each represented as an hypothetical entity during which certain unique operations an performed an incoming information.

A mathematical model for human brain cooling during cold-water near-drowning.

A two-dimensional mathematical model was developed to estimate the contributions of different mechanisms of brain cooling during cold-water near-drowning. Mechanisms include 1) conductive heat loss through tissue to the water at the head surface and in the upper airway and 2) circulatory cooling to aspirated water via the lung and via venous return from the scalp. The model accounts for changes in boundary conditions, blood circulation, respiratory ventilation of water, and head size. Results indicate that conductive heat loss through the skull surface or the upper airways is minimal, although a small child-sized head will conductively cool faster than a large adult-sized head. However, ventilation of cold water may provide substantial brain cooling through circulatory cooling. Although it seems that water breathing is required for rapid "whole" brain cooling, it is possible that conductive cooling may provide some advantage by cooling the brain cortex peripherally and the brain stem centrally via the upper airway.

Natural Heuristic Dynamic Programming for Dynamic Systems Control

Heuristic Dynamic Programming (HDP) is the simplest kind of Adaptive Critic (Werbos, 1992). It can be used to maximize or minimize any utility function, such as total energy or trajectory error, of a system over time in a noisy environment. This article proposes a new version of HDP, called NHDP (Natural Heuristic Dynamic Programming). This new version incorporates basic HDP algorithm with the following features:(i) use of Trajectory Pattern Method to guarantee smoothness of trajectory and control signals; (ii) use multiple critic networks to localize effect of each parameter mimicking the natural biological model of human brain; and (iii) allow the controller to learn from slow to fast motion, analogous to the natural learning behavior of humans. A simple dynamic system is used to illustrate NHDP.

Brain Weight Does Not Decrease with Age in Adult Rhesus Monkeys

Cross-sectional studies on adult human autopsy material have shown that younger cohorts have heavier brains than older groups. We sought to determine whether a similar pattern is present in the rhesus monkey, a species that serves as a useful model of human brain and cognitive aging. Data were obtained from necropsies of 399 rhesus monkeys (180 females; 219 males), of ages covering the entire adult lifespan of this species. In addition to fresh brain weight, variables considered were age, sex, body weight, heart weight, identity of the prosector, and circumstance of death. Initial bivariate analyses revealed a significant sex difference in brain weight (mean for males: 96.1g; for females: 86.1g; p < 0.001), as well as significant correlations of brain weight with body weight ( r = 0.20, p < 0.01 for females; r = 0.27, p < 0.001 for males), and heart weight ( r = 0.27, p < 0.001 for females; r = 0.38, p < 0.001 for males). Identity of prosector, circumstance of death, and age were not significantly related to brain weight in bivariate analyses. Multiple linear regression, controlling for possible confounding effects of body weight and sex, also suggested that brain weight is stable throughout adulthood in the rhesus monkey.

A boundary element method for simulation of deformable objects

In this paper, a boundary element method is first applied to real-time animation of deformable objects and to simplify data preparation. Next, the visible external surface of the object in deforming process is represented by B-spline surface, whose control points are embedded in dynamic equations of BEM. Finally, the above method is applied to anatomical simulation. A pituitary model in human brain, which is reconstructed from a set of anatomical sections, is selected to be the deformable object under action of virtual tool such as scalpel or probe. It produces fair graphic realism and high speed performance. The results show that BEM not only has less computational expense than FEM, but also is convenient to combine with the 3D reconstruction and surface modeling as it enables the reduction of the dimensionality of the problem by one.

Evaluation of monoaminergic neurotransmitters in the acute focal ischemic human brain model by intracerebral in vivo microdialysis

The release of neurotransmitters principally glutamate during cerebral ischemia has been extensively studied. It is well recognized that ischemia induced release of glutamate plays a key role in "excitotoxic" neuronal death. The role of monoaminergic neurotransmitters is however unclear. The purpose of this study was to evaluate the extracellular norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA) and serotonin (5-HT) under varied degrees of ischemia in the acute focal ischemic model of the human brain by in-vivo microdialysis. The ischemic response of these amines was correlated with the glutamate levels. Our study concludes that these amines and metabolites can be detected in the human "stroke" model. No marked fluctuations were noted in the levels of norepinephrine and DOPAC. However, significant changes to partial and total ischemia were noted in the extracellular levels of 5-HIAA and 5-HT. These compounds showed a dramatic increase with the onset of ischemia with higher detectable levels in the partial ischemic state in comparison to the total ischemic dialysate levels. The exact role played by the differential increase in the levels of 5-HT to the other catecholamines in the pathogenesis of ischemic neuronal damage remains unclear and warrants further study.

SS-9-2 Localized magnetic stimulation of the human brain and nerve excitation models

SS-9-2 Localized magnetic stimulation of the human brain and nerve excitation models

Recent Advances in Biomechanics of Brain Injury Research: A Review

Biomechanics of cerebral trauma attempts to delineate the dynamic response of the cranial vault contents to a direct or indirect impact to the head. Consequently, brain injury mechanisms and associated tolerance to impact can be deduced by establishing a relationship between neurological deficit and mechanical dosage. The resulting information is invaluable to brain injury prevention and diagnosis. This paper presents an overview of our recent research on head injury focusing on establishing brain injury biomechanics by developing a comprehensive and validated mathematical model. To achieve our goal, we developed a comprehensive three-dimensional finite element human head model, finite element porcine head models, and sensors to monitor head kinematics and brain strains by neutral density accelerometers. The information obtained from this research thus far provided a predictive and somewhat validated mathematical model of the head, which clearly shows a correspondence between brain mechanical response and experimentally observed injuries.

Development of tissue level brain injury criteria by finite element analysis.

A three-dimensional finite element model of the direct cortical impact experiment was built and a preliminary validation against mechanical response was completed. The motion of the impactor was enforced in the model by applying the same acceleration history as that of the experimental impactor. A nonlinear contact surface algorithm was used for impactor-brain interface with the ABAQUS general purpose finite element program. The resulting motion of the impactor and the contacting node in the brain model confirmed that the impactor moved realistically and contacted the brain surface. The pressure generated in the model compared favorably with that measured by a pressure transducer in the experiment. The pattern of high shear deformation generated at the impact site in the model was similar to the pattern of contusion hemorrhage seen in the experiment. The pressure generated at the impact site propagated to the skull-brain boundary, especially, at the posterior margin of the cerebellum. Analysis of experimental data using a biomechanically validated finite element model will enable determination of tissue-level injury criteria for application in human brain models to predict head injury potential in contact, noncontact, or side impact situations.

Influence of chronic cocaine on monoamine neurotransmitters in human brain and animal model: preliminary observations.

Annals of the New York Academy of SciencesVolume 654, Issue 1 p. 461-463 Influence of Chronic Cocaine on Monoamine Neurotransmitters in Human Brain and Animal Model: Preliminary Observations J. M. WILSON, J. M. WILSON Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada M5T 1R8 University of Toronto Toronto, Ontario, CanadaSearch for more papers by this authorJ. N. NOBREGA, J. N. NOBREGA Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada M5T 1R8 University of Toronto Toronto, Ontario, CanadaSearch for more papers by this authorW. CORRIGALL, W. CORRIGALL Addiction Research Foundation, University of Toronto Toronto, Ontario, Canada University of Toronto Toronto, Ontario, CanadaSearch for more papers by this authorK. SHANNAK, K. SHANNAK Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada M5T 1R8Search for more papers by this authorJ. H. N. DECK, J. H. N. DECK Addiction Research Foundation, University of Toronto Toronto, Ontario, CanadaSearch for more papers by this authorS. J. KISH, S. J. KISH Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada M5T 1R8 University of Toronto Toronto, Ontario, CanadaSearch for more papers by this author J. M. WILSON, J. M. WILSON Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada M5T 1R8 University of Toronto Toronto, Ontario, CanadaSearch for more papers by this authorJ. N. NOBREGA, J. N. NOBREGA Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada M5T 1R8 University of Toronto Toronto, Ontario, CanadaSearch for more papers by this authorW. CORRIGALL, W. CORRIGALL Addiction Research Foundation, University of Toronto Toronto, Ontario, Canada University of Toronto Toronto, Ontario, CanadaSearch for more papers by this authorK. SHANNAK, K. SHANNAK Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada M5T 1R8Search for more papers by this authorJ. H. N. DECK, J. H. N. DECK Addiction Research Foundation, University of Toronto Toronto, Ontario, CanadaSearch for more papers by this authorS. J. KISH, S. J. KISH Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada M5T 1R8 University of Toronto Toronto, Ontario, CanadaSearch for more papers by this author First published: June 1992 https://doi.org/10.1111/j.1749-6632.1992.tb25999.xCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume654, Issue1The Neurobiology of Drug and Alcohol AddictionJune 1992Pages 461-463 RelatedInformation

A normal human brain cell aggregate model for neurobiological studies.

A new in vitro model of normal human brain has been developed in which fetal human brain cells form three-dimensional aggregates that can be maintained for up to 60 days in culture. Cells appear fully differentiated at the time of initiation in culture; the predominant cells identified were astrocytes, neurons, and oligodendrocytes with myelin, with occasional ependymal cells and macrophages. The specific arrangement and numbers of neural cells within aggregates differed among brain specimens. Cell kinetics studies detected DNA synthesis throughout the culture interval. Aggregates cocultured with a human malignant glioma cell line (U251-MG) were progressively invaded by tumor cells. In aggregates infected with human cytomegalovirus (CMV), intracellular viral replication and morphologic changes characteristic of human brain infection with this pathogen were seen. This model of brain aggregates should prove valuable for multidisciplinary studies in human neurobiology, particularly in the fields of developmental neurobiology, neuro-oncogenesis, tumor cell invasion, and species-specific viral infection of the central nervous system.

Heating of spherical versus realistic models of human and infrahuman heads by electromagnetic waves

A numerical method based on a tensor integral equation has been employed to quantify the induced EM heating in realistic models of the human and infrahuman head. The head consists of a brain of realistic shape and eyes that are surrounded by a bony structure. The numerical method has also been used to determine the induced EM heating in spherical models of human and infrahuman heads and brains. The EM heating induced in the brain of the realistic model is lower than that induced in the brain of the spherical model. The bony stucture of the skull tends to attenuate heating of the brain, including the eyes.

Structural alterations in neurons of aged canine neocortex: A Golgi study

Golgi impregnation techniques were used to evaluate the morphologic changes in the pyramidal cells of the frontal cortex of six aged dogs of various breeds (13 to 18 years old) in comparison with three young mongrels (2 to 4 years old). These studies reveal characteristic alterations which are in good agreement with changes described previously in aged human cortex. These alterations, which, if regarded as a dynamic histopathologic sequence of neuronal deterioration in response to aging, include distortion of neuronal soma, loss of dendritic spines often concommitant with zones of dendritic varicosities, and shrinkage of the vertical and, particularly, the horizontal dendritic branches. Apical dendrites with tortuous ascending paths as well as apparent proliferation of new dendritic spines are also described. The aged canine cortex seems to demonstrate many of the important characteristics associated with the constellation of pathologic changes found in the senescent human brain. These changes are often only minimally present in the rodent. The aged dog, which in addition exhibits typical senile plaques, may therefore be a valuable animal model for the aging human brain.