The aphasias: fall and renaissance of the neurological model?
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Aphasia↗
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Magnetic resonance microscopy in neurologic models.
Magnetic resonance imaging techniques have been developed to permit imaging with slice thickness less than 1 mm and pixels of 50 x 50 microns. Special purpose gradient and radiofrequency coils and three-dimensional imaging techniques enable acquisition of images with sufficient signal to noise to utilize these microscopic picture elements. Live 200 g rats were imaged enabling clear definition of gray and white matter structures. Examples include the Sylvian aqueduct and the substantia nigra. Three-dimensional microscopic images of live chick embryos enabled definition of ventricles and brain parenchyma as well as measurement of T1 over the set of 16 contiguous 1.2 mm slices.
Animals↗
Bilateral alteration in stepping pattern after unilateral motor cortex injury: a new test strategy for analysis of skilled limb movements in neurological mouse models.
Mice are becoming increasingly popular to model neurological disease and motor system dysfunction. For evaluation of discrete, chronic motor impairments, skilled limb movements represent a valuable extension of standard mouse test batteries. This study introduces an efficient and sensitive test strategy for comprehensive assessment of skilled fore- and hind-limb stepping in mice. Adult C57BL/6 mice were trained and video-recorded in two walking tasks, the widely used rotorod test and a new ladder rung task. The animals then received a unilateral ischemic lesion in the motor cortex forelimb and hind limb area and were video-recorded on days 12 and 26 post-lesion. Forelimb and hind limb stepping movements were rated using a combination of endpoint measures and qualitative assessment. The results showed that while animals maintained a weight-supported gait, posture and stepping movements were abnormal at both post-operative intervals. The rotorod analysis revealed stepping deficits in both forelimbs that led to adoption of compensatory movement strategies. The ladder rung task revealed stepping errors in ipsi- and contralateral fore- and hind-limbs. The findings demonstrate that this test strategy provides comprehensive assessment of motor impairments in mice and that qualitative movement analysis is a valuable tool for elaborating subtle motor disturbances.
Animals↗
Chemokines in neurological disease models: correlation between chemokine expression patterns and inflammatory pathology.
We have recently determined chemokine expression profiles in a variety of models of neural trauma and immune-inflammation. The results indicate the following: (1) Chemokine expression in posttraumatic inflammation is generally restricted to the monocyte chemoattractant MCP-1, and occurs before hematogenous cell entry into neural tissues. Therefore MCP-1 is an excellent candidate for a mediator of leukocyte recruitment in these settings. (2) Chemokine expression in immune-inflammation is diverse and includes both alpha- and beta-chemokines. Chemokine production can be attributed to parenchymal and infiltrating cell populations. Early signs of inflammation precede chemokine expression, which is believed to exert the crucial function of amplifying the immune-mediated inflammatory reaction. These observations provide a basis for evaluating model neurological disorders in transgenic mice that express chemokines ectopically or in mice that are deficient in chemokine ligands or receptors as a consequence of gene targeting. Ultimately, a clear definition of roles of chemokines and their receptors in neurological diseases will suggest rational intervention.
Animals↗
[Some theoretical aspects of models. Modelling in neurology].
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Models, Theoretical↗
Animal models of neurological deficits: how relevant is the rat?
Animal models of neurological deficits are essential for the assessment of new therapeutic options. It has been suggested that rats are not as appropriate as primates for the symptomatic modelling of disease, but a large body of data argues against this view. Comparative analyses of movements in rats and primates show homology of many motor patterns across species. Advances have been made in identifying rat equivalents of akinesia, tremor, postural deficits and dyskinesia, which are relevant to Parkinson's disease. Rat models of hemiplegia, neglect and tactile extinction are useful in assessing the outcome of ischaemic or traumatic brain injury, and in monitoring the effects of therapeutic interventions. Studies in rodents that emphasize careful behavioural analysis should continue to be developed as effective and inexpensive models that complement studies in primates.
Animals↗
Transgenic and knock-out mice: models of neurological disease.
Besides providing useful model systems for basic science, studies based on modification of the mammalian germ line are changing our understanding of pathogenetic principles. In this article, we review the most popular techniques for generating specific germ line mutations in vivo and discuss the impact of various transgenic models on the study of neurodegenerative diseases. The "gain of function" approach, i.e., ectopic expression of exogenous genes in neural structures, has deepened our understanding of neurodegeneration resulting from infection with papova viruses, picorna viruses, and human retroviruses. Further, inappropriate expression of mutated cellular molecules in the nervous system of transgenic mice is proving very useful for studying conditions whose pathogenesis is controversial, such as Alzheimer's disease and motor neuron diseases. As a complementary approach, ablation of entire cell lineages by tissue-specific expression of toxins has been useful in defining the role of specific cellular compartments. Modeling of recessive genetic diseases, such as Lesch-Nyhan syndrome, was helped by the development of techniques for targeted gene deletion (colloquially termed "gene knock-out"). Introduction of subtle homozygous mutations in the mouse genome was made possible by the latter approach. Such "loss of function" mutants have been used for clarifying the role of molecules thought to be involved in development and structural maintenance of the nervous system, such as the receptors for nerve growth factor and the P0 protein of peripheral myelin. In addition, these models are showing their assets also in the study of enigmatic diseases such as spongiform encephalopathies.
Alzheimer Disease↗
Support of progress in clinical neurology by models of genetic regulation.
Many neurological disorders are based on mutations in 1 or more genes. To understand and optimally treat these disorders, it is necessary to understand the functions and regulation of the genes involved. It has become apparent that intuitive descriptions of gene regulation are often insufficient. A mathematical description adds precision and detail. Therefore, a mathematical description is important for networks of genes that underlie development, synaptic plasticity, and other complex biological processes. A mathematical description is also important to represent the combined effects of multiple genes that contribute to the phenotype of complex neurological disorders. In such gene networks, it is common for some of the gene products to regulate the expression of other network members. Also, the expression of all or some network members is commonly coregulated. Gene product proteins that regulate transcription are termed transcription factors (TFs), and many genes are activated by multiple TFs.
Animals↗
Modeling the neurological control of human movements.
Although computer models have been extensively used in recent years to understand the way physical systems operate and interact, the enormous power of mathematical modeling and computer simulations has been difficult to implement for the benefit of neuroscientists studying the human motor control system. Nevertheless, homeomorphic models are now being used to explain and predict the neural and biomechanical aspects of different human movements. This paper argues for the importance of regarding model simulations as a supplementary approach to traditional methods of experimental investigation by drawing examples from both the experimental and the modeling literature. The discussion focuses on studies of the triphasic control signal for fast, goal-directed movements and on aspects of sampled data control for slow, tracking movements. The aim of this viewpoint article is to promote a more widespread use of modeling and simulation in the field of motor control.
Journal Article↗
A discriminative prediction model of neurological outcome for patients undergoing surgery of brain arteriovenous malformations.
BACKGROUND AND PURPOSE: To develop and validate a discriminative model for predicting neurological morbidity after brain arteriovenous malformation (bAVM) surgery. METHODS: Of 233 consecutive, prospectively enrolled patients undergoing bAVM surgery, the first 175 were used to derive, and the last 58 to validate, the prediction model. Demographic and angiographic factors were related to modified Rankin Scale scores assigned before, within 72 hours, at 7 days and at > or =1 year after surgery to seek predictors of postoperative neurological deficits (modified Rankin Scale score > or =3). These factors included nidus size, eloquence, venous drainage, diffuseness, white matter configuration, arterial perforator supply and associated aneurysms. RESULTS: Brain eloquence, diffuse nidus and deep venous drainage were significant predictors of early disabling neurological deficits (odds ratios of 4.33, 3.49 and 2.38, respectively). The rounded odds ratios form a weighted 9-point prediction model (maximum scores for eloquence+diffuseness+deep drainage=4+3+2). The score discriminated the probability of experiencing both early (first week) and permanently (at > or =1 year) disabling neurological deficits as follows: 0 to 2: 1.8%, 3 to 5: 17.4%, 6 to 7: 31.6%, >7: 52.9% for early and 0 to 2: 1.8%, 3 to 5: 4.4%, 6 to 7: 18.4%, >7: 32.4% for permanently disabling outcomes. The discrimination of the model was 0.80 with 2.8% optimism. Validation in the second patient cohort revealed good performance at risk stratification. CONCLUSIONS: Relative weights assigned to brain eloquence, diffuse nidus morphology and deep venous drainage of a bAVM provide a simple and discriminative prediction model for neurological outcome after bAVM surgery.
Adolescent↗
A model for neurologic sources of aperiodicity in vocal fold vibration.
The time course of a force twitch in the thyroarytenoid muscle is modeled, and trains of twitches are summed to simulate force tetani. By incorporating means and standard deviations of motoneuron firing rates, and by applying random phase relationships between simulated motor units, a quantitative model of the ripple of vocal fold tension is obtained. From this ripple, perturbations in fundamental frequency are calculated as a function of the number of motor units in the muscle, the mean and standard deviation of the firing rate of dominant motoneurons, and the variability in the size (twitch amplitude) of the motor units. Predicted perturbations range between 0.2% and 1.2%, depending on the choice of parameters. Perturbation decreases with the number of motor units and with increased mean firing rate, but increases with the variability in motor unit size and with variability in the firing rate. Techniques are discussed by which neurologic jitter might be isolated from other sources of irregularity in vocal fold vibration.
Action Potentials↗
Noise in models of neurological and psychiatric disorders.
The concept of noise has only recently been applied to modelling neuropsychiatric disorders. Two examples of such models are presented. 1. A phantom limb is a neurological condition after the amputation of an extremity. It consists of sensations of the presence of the lost limb and has been attributed to cortical as well as non-cortical mechanisms. A neural network model of phantom limbs is proposed which can parsimoniously account for a large number of clinical features and recent findings of cortical map plasticity after deafferentation. In trained self-organizing feature maps, deafferentation was simulated. Reorganization is shown to be driven by input noise. According to the model, the production of input noise by the deafferented primary sensory neuron drives cortical reorganization in amputees. No such noise is generated and/or conducted to the cortex in paraplegics. 2. Several clinical features of schizophrenia have been related to the ratio of signal to noise in neuronal information processing. In particular, dopamine--which has been implicated in the causation of schizophrenia for decades--has been proposed to modulate signal-to-noise ratio. Data are presented which suggest that schizophrenic thought disorder is the result of a hypodopaminergic state and concomitant increased effects of noise in semantic information processing. Possible functions of noise in the nervous systems are discussed.
Computer Simulation↗
Microarray analysis of nonhuman primates: validation of experimental models in neurological disorders.
Nonhuman primates (NHPs) have provided robust experimental animal models for many human-related diseases due to their similar physiologies. Nonetheless, profound differences remain in the acquisition, progression, and outcome of important diseases such as AIDS and Alzheimer's, for which the underlying basis remains obscure. We explored the utility of human high-density oligonucleotide arrays to survey the transcription profile of NHP genomes. Total RNA from prefrontal cortices of human (Homo sapiens), common chimpanzee (Pan troglodytes), cynomolgous macaque (Macaca fascicularis), and common marmoset (Callithrix jacchus) was labeled and hybridized to Affymetrix U95A GeneChip probe arrays. Corresponding data obtained previously from common chimpanzee and orangutan (Pongo pygmaeus) were added for comparison. Qualitative (present or not detected) and quantitative (expression level) analysis indicated that many genes known to be involved in human neurological disorders were present and regulated in NHPs. A gene involved in dopamine metabolism (catechol-O-methyltransferase) was absent in macaque and marmoset. Glutamate receptor 2 was up-regulated, and transcription-associated genes were down-regulated in NHPs compared with humans. We demonstrate that transcript profiling of NHPs could provide comparative genomic data to validate and better focus experimental animal models of human neurological disorders.
Adult↗
Effect of dexamethasone on monoamine and metabolite levels in a brain-tumor model.
Neurological improvement in brain-tumor patients treated with dexamethasone (DEX) precedes a reduction in peritumor brain edema. In the study reported here, levels of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT), homovanillic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA) and tissue water content were measured in grey and white matter adjacent to a 9L glioma in the cat to study DEX-neurotransmitter interactions as possible mechanisms for the acute neurological effects of DEX. Tumor-bearing and control cats were treated or not treated with DEX (0.25 mg/kg IV, 0.25 mg/kg IM) with 0.25 mg/kg IM repeated once (DEX 1) or 3 times (DEX 2) 6 hr apart. In control animals DEX 1 treatment led to significant decreases in concentration of DOPAC; DEX 2 treatment led to increases in HVA and 5-HIAA. Peritumor grey matter from untreated tumor-bearing animals had decreased levels of NA and DA and the metabolite DOPAC with no changes in 5-HT and 5-HIAA. DEX 2 but not DEX 1 resulted in a normalization (increase) in peritumor levels of DA and DOPAC. Neither dose of DEX reduced white matter edema. These findings suggest that the acute beneficial effect of DEX on neurological status may be due to alleviation of neurotransmitter amine and metabolite depletion.
Animals↗
[The model of neurological care needs in Valencian community. Commission of the analysis of the quality of SVN].
The model that will based any specialized attention in any healthy area depends the necessity of special and primary cares and the criteria of specialized practitioners on the type of patients what should be treated. We interview following a questionnaire on that question the neurologists of Valencian Community in order to know their opinion. The questionnaire includes 47 neurological topics and we ask the percentage of patients who should be evaluated as first visit and as follow-up visits. We used the formula proposed by Kurtzke in 1986 in order to calculate the neurological time. The response rate obtained was 30%. The whole neurological time was 4,600 hours per 100,000 inhabitants yearly, that means 6.9 neurologists-type per 100,000 inhabitants. These data suggest that Valencian neurologists agree a model of direct neurological care, including diagnosis and follow-up of all neurological topics. These data are similar to that obtained in interviews to primary physicians in different healthy areas in the Community and confirms the evolution of neurological care to a model similar to that in the United States. The topic that require more than 100 hours by year are: migraine (1,731) lumbar backache (685), stroke (306), seizures (248), Down's syndrome (175.5), alcoholism (150), zoster (122), severe cranial trauma (105) and dementia (103).
Adult↗
[Study of the effect of the cDNA for the human apolipoprotein A-I gene in transgenic rabbits: modeling the neurological syndrome of human Tangier disease].
Two transgenic rabbits which carried human apolipoprotein A-1 (apo A-1) cDNA under mouse ribosomal protein L/32 promoter were obtained. The effectiveness of transgenosis was confirmed by DNA dot/blot and Southern blot hybridizations. Both transgenic animals had paralyses of fore or fore and high limbs. Electron microscopy demonstrated distinct degradative changes of those parts of spinal cord which were responsible for leg skeletal muscle innervation. RNA dot/blot hybridization showed transgene expression in liver and brain but not in kidney of adult transgenic animal. However, analysis of blood serum lipids and immunochemical determinations gave no indications of the presence of human apo A-1 in adult transgenic rabbit. The data obtained allow us to suggest that the observed pathology was due to interference of native and foreign protein products of apo A-1 gene expression in CNS in the course of embryo development. This suggestion was supported by results of in situ hybridization of 5- and 9-week human embryo sections with apo A-1 cDNA, showing effective expression of apo A-1 gene in neural cells of CNS. Results of transgenosis may be viewed as modeling of the neurological syndrome of human Tangier disease.
Animals↗
Establishment of modified chimeric mice using GFP bone marrow as a model for neurological disorders.
Chimeric mice stably reconstituted with bone marrow cells represent a good model for analysis of the mechanism of bone marrow cell infiltration in the brain. However, in preparing chimeric mice, irradiation of the recipient mice is necessary to kill their own bone marrow before transplantation, which induces gliosis and inflammatory response by activation of astrocytes and microglia in the brain. Here, we determined the most suitable dose of irradiation associated with the least brain damage before transplantation for reconstitution of chimeric mice, using FACS analysis. Our mouse model of 10 Gy body/5 Gy head irradiation should be useful for investigating the mechanism(s) of microglial activation in various neurological disorders such as stroke, Alzheimer's disease and Parkinson's disease.
Animals↗
Capacity to vary writing hand/posture in relation to the Levy and Reid model for control of writing.
Inherent in Levy and Reid's (1978) neurological model for the control of writing hand/posture were implications pertaining to the capacity of people to vary their hand/posture when writing. These implications were formulated into the writing variation hypothesis. The skill with which right-normal, left-inverted, and left-normal writers were able to write using hand/postures other than their preferred one was examined. The resulting performance was incompatible with Levy and Reid's neurological model. Whether or not subjects wrote with their preferred hand seemed more important than which posture they used.
Journal Article↗