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PubMed2006

Haemodynamics and wall remodelling of a growing cerebral aneurysm: a computational model.

We have developed a computational simulation model for investigating an often postulated hypothesis connected with aneurysm growth. This hypothesis involves a combination of two parallel and interconnected mechanisms: according to the first mechanism, an endothelium-originating and wall shear stress-driven apoptotic behavior of smooth muscle cells, leading to loss of vascular tone is believed to be important to the aneurysm behavior. Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All resistance and capacitance vessels under basal conditions exhibit some degree of smooth muscle contraction that determines the diameter, and hence tone, of the vessel. The second mechanism is connected to the arterial wall remodeling. Remodeling of the arterial wall under constant tension is a biomechanical process of rupture, degradation and reconstruction of the medial elastin and collagen fibers. In order to investigate these two mechanisms within a computationally tractable framework, we devise mechanical analogues that involve three-dimensional haemodynamics, yielding estimates of the wall shear stress and pressure fields and a quasi-steady approach for the apoptosis and remodeling of the wall. These analogues are guided by experimental information for the connection of stimuli to responses at a cellular level, properly averaged over volumes or surfaces. The model predicts aneurysm growth and can attribute specific roles to the two mechanisms involved: the smooth muscle cell-related loss of tone is important to the initiation of aneurysm growth, but cannot account alone for the formation of fully grown sacks; the fiber-related remodeling is pivotal for the latter.

Biomechanical Phenomena↗
PubMedDate not supplied

3D computer modeling of human cardiogenesis.

We obtained digitized histological serial sections of three human embryos of different stages from the Armed Forces Institute of Pathology from which contours of cardiac structures were digitally traced. Traces were placed in register for the construction of wire frame models using Silicon Graphics Incorporated 3D computer modeling software (Alias/Wavefront) and for surface rendering to demonstrate internal and external developmental anatomy. The models allowed stage-to-stage morphing and physical model construction using stereolithography. These innovations in embryo reconstruction not only facilitate medical education, they also serve as new tools for scientific investigation of cardiogenesis and congenital heart disease.

Computer Simulation↗
PubMedDate not supplied

Sequence seeking and counter streams: a computational model for bidirectional information flow in the visual cortex.

A computational model is proposed for some general aspects of information flow in the visual cortex. The basic process, called "sequence seeking," is a search for a sequence of mappings, or transformations, linking source and target patterns. The process has two main characteristics: it is bidirectional, bottom-up as well as top-down, and it explores in parallel a large number of alternative sequences. This operation is performed in a "counter streams" structure, in which multiple sequences are explored along two complementary pathways, an ascending and a descending one, seeking to meet. A biological embodiment of this model in cortical circuitry is proposed. The model serves to account for known aspects of cortical interconnections and to derive new predictions.

Animals↗
PubMed2005

From brainstem to cortex: computational models of saccade generation circuitry.

The brain circuitry of saccadic eye movements, from brainstem to cortex, has been extensively studied during the last 30 years. The wealth of data gathered allowed the conception of numerous computational models. These models proposed descriptions of the putative mechanisms generating this data, and, in turn, made predictions and helped to plan new experiments. In this article, we review the computational models of the five main brain regions involved in saccade generation: reticular formation saccadic burst generators, superior colliculus, cerebellum, basal ganglia and premotor cortical areas. We present the various topics these models are concerned with: location of the feedback loop, multimodal saccades, long-term adaptation, on the fly trajectory correction, strategy and metrics selection, short-term spatial memory, transformations between retinocentric and craniocentric reference frames, sequence learning, to name the principle ones. Our objective is to provide a global view of the whole system. Indeed, narrowing too much the modelled areas while trying to explain too much data is a recurrent problem that should be avoided. Moreover, beyond the multiple research topics remaining to be solved locally, questions regarding the operation of the whole structure can now be addressed by building on the existing models.

Animals↗
PubMedDate not supplied

Using computational modeling to transform nursing data into actionable information.

Transforming organizational research data into actionable information nurses can use to improve patient outcomes remains a challenge. Available data are numerous, at multiple levels of analysis, and snapshots in time, which makes application difficult in a dynamically changing healthcare system. One potential solution is computational modeling. We describe our use of OrgAhead, a theoretically based computational modeling program developed at Carnegie Mellon University, to transform data into actionable nursing information. We calibrated the model by using data from 16 actual patient care units to adjust model parameters until performance of simulated units ordered in the same way as observed performance of the actual units 80% of the time. In future research, we will use OrgAhead to generate hypotheses about changes nurses might make to improve patient outcomes, help nurses use these hypotheses to identify and implement changes on their units, and then measure the impact of those changes on patient outcomes.

Computational Biology↗
PubMedDate not supplied

Validation of a detailed computer model for the electric fields in the brain.

A computer model has been designed for the calculation of the electrical fields in the head, based on the finite difference method. This method has not previously been applied for head modelling. The model was validated by using three concentric spheres and comparing it with an analytic model. Three levels of accuracy were tested. The forward solutions show that the finite difference algorithm works correctly and, by selecting the size of the volume elements properly, accurate results are obtained. The model will be applied to accurate and realistic geometries of the human head obtained from magnetic resonance images.

Brain↗
PubMed1995

Initialization of warfarin dosages using computer modeling.

OBJECTIVE: Software incorporating warfarin pharmacokinetics and pharmacodynamics, as well as a Bayesian regression method, was evaluated for accuracy in predicting steady-state dosages of warfarin during initialization of anticoagulation therapy. DESIGN: A cohort study was used to compare computer predictions with physician-determined doses during a retrospective chart review of 42 patients. PATIENTS: Forty-two patient charts were selected for monitoring anticoagulation initialization therapy. Of the 42 patients reviewed, 22 were excluded on the following bases: uncontrolled congestive heart failure; ongoing treatment with medications that interfered with warfarin metabolism or displaced warfarin from protein binding sites; recent treatment with fresh frozen plasma or vitamin K; or any bleeding disorders, sepsis, malabsorption or significant changes in liver and/or renal function. MAIN OUTCOME MEASURES: Using physician-determined International Normalized Ratios (INRs) as target levels for the software, the number of INR feedbacks needed to stabilize blood drug levels during initialization were compared between physicians and computer forecasting. Population parameters and sequentially measured INRs were used for evaluation. RESULTS: Current oral anticoagulation protocols require significantly more measured INRs than computer forecasting to achieve steady-state dosages (9.5 v 4.4, respectively, p < 0.01). Physicians showed a statistically significant pattern of underdosing patients (4.3 v 1.7 subtherapeutic INRs, respectively, p < 0.01). Computer predictions tended to overdose patients but did not significantly increase the number of supratherapeutic INRs. This study showed that five INR inputs consistently gave accurate steady-state dosage predictions, and in many ways computer modeling was more effective than clinician-determined steady-state dosing in warfarin initialization. CONCLUSIONS: Computer modeling provides a reliable means of predicting initialization dosages for warfarin anticoagulation therapy with five INR inputs and therefore has merit in the clinical setting if used with sound clinical judgment.

Adult↗
PubMed2003

Biologically motivated computational modeling of chloroform cytolethality and regenerative cellular proliferation.

Chloroform is a nongenotoxic-cytotoxic carcinogen in rodents. As such, events related to cytotoxicity are the driving force for cancer induction. In this paper we extended an existing physiologically based pharmacokinetic (PBPK) model for chloroform to describe a plausible mechanism linking the hepatic metabolism of chloroform to hepatocellular killing and regenerative proliferation. The key aspects of this mechanism are (1) the production of damage at a rate proportional to the rate of metabolism predicted by the PBPK model, (2) the saturable repair of the damage, (3) the stimulation of the cell death rate by damage, and (4) the stimulation of the cell division rate as a function of the difference between the control and exposed numbers of cells. This extension allows the simulation of the labeling index and comparison with labeling index data. Data from a previously published chloroform-inhalation study with female B6C3F1 mice that determined cytolethality and regenerative cellular proliferation following exposures of varying concentrations and exposure durations were used for model calibration. Both threshold and low-dose linear linkages between chloroform-induced damage and cell death rate provided visually good fits to the labeling index data after formal optimization of the adjustable parameters, and there was no statistical difference between the fits of the two models to the data. Biologically motivated computational modeling of chloroform-induced cytolethality and regenerative proliferation is a necessary step in the quantitative evaluation of the hypothesis that chloroform-stimulated cell proliferation predicts the rodent tumor response.

Administration, Inhalation↗
PubMed2005

Testing two predictions for fracture load using computer models of trabecular bone.

Aging induces several types of architectural changes in trabecular bone including thinning, increased levels of anisotropy, and perforation. It has been determined, on the basis of analysis of mathematical models, that reduction in fracture load caused by perforation is significantly higher than those due to equivalent levels of thinning or anisotropy. The analysis has also provided an expression which relates the fractional reduction of strength tau to the fraction of elements nu that have been removed from a network. Further, it was proposed that the ratio Gamma of the elastic constant of a sample and its linear response at resonance can be used as a surrogate for tau. Experimental validation of these predictions requires following architectural changes in a given sample of trabecular bone; techniques to study such changes using microcomputed tomography are only beginning to be available. In the present study, we use anatomically accurate computer models constructed from digitized images of bone samples for the purpose. Images of healthy bone are subjected to successive levels of synthetic degradation via surface erosion. Computer models constructed from these images are used to calculate their fracture load and other mechanical properties. Results from these computations are shown to be consistent with predictions derived from the analysis of mathematical models. Although the form of tau(nu) is known, parameters in the expression are expected to be sample-specific, and hence nu is not a reliable predictor of strength. We provide an example to demonstrate this. In contrast, analysis of model networks shows that the linear part of tau(Gamma) depends only on the structure of trabecular bone. Computations on models constructed from samples of iliac crest trabecular bone are shown to be in agreement with this assertion. Since Gamma can be computed from a vibrational assessment of bone, we argue that the latter can be used to introduce new surrogates for bone strength and hence diagnostic tools for osteoporosis.

Bone Density↗
PubMed1997

A simple computer model to simulate ECG based on ionic channels.

The presented computer model reconstructs the ECG with 500 myocardium cells based on seven ionic channels. The low hardware-requirement and the exact demonstration of physiological and pathophysiological coherence make this simulation model very useful for medical scientific education.

Cell Hypoxia↗
PubMed2006

Making working memory work: a computational model of learning in the prefrontal cortex and basal ganglia.

The prefrontal cortex has long been thought to subserve both working memory (the holding of information online for processing) and executive functions (deciding how to manipulate working memory and perform processing). Although many computational models of working memory have been developed, the mechanistic basis of executive function remains elusive, often amounting to a homunculus. This article presents an attempt to deconstruct this homunculus through powerful learning mechanisms that allow a computational model of the prefrontal cortex to control both itself and other brain areas in a strategic, task-appropriate manner. These learning mechanisms are based on subcortical structures in the midbrain, basal ganglia, and amygdala, which together form an actor-critic architecture. The critic system learns which prefrontal representations are task relevant and trains the actor, which in turn provides a dynamic gating mechanism for controlling working memory updating. Computationally, the learning mechanism is designed to simultaneously solve the temporal and structural credit assignment problems. The model's performance compares favorably with standard backpropagation-based temporal learning mechanisms on the challenging 1-2-AX working memory task and other benchmark working memory tasks.

Algorithms↗
PubMedDate not supplied

Computer modelling studies of ribonuclease T1-2'-deoxy-2'-fluoroguanylyl- (3',5')-cytidine complex.

The mode of binding of the substrate analog 2'-deoxy-2'-fluoroguanylyl- (3',5')-cytidine (GfpC) to RNase T1 was determined by computer modelling studies. The results obtained are in good agreement with the observations of 1H-nmr studies. The modes of binding of the substrate analog GfpC and the substrate GpC to the enzyme RNase T1 have been compared. Though the guanine base favours to occupy the same site of the enzyme in both the complexes, significant differences are observed in the local environment around the 2'-substituent group of guanosine ribose moiety. In the RNase T1-GpC complex, the 2'-OH group is in close proximity to the side chain carboxylic acid of Glu58 which leads to the formation of a hydrogen bond. However, in the RNase T1-GfpC complex, 2'-fluorine is positioned away from Glu58 due to electrostatic repulsion and instead forms a hydrogen bond with His40 imidazolium group. The results obtained rule out the possibility of His40 serving as the base group in catalysis as suggested by 1H-nmr studies and further support the primary role assigned to Glu58 as the general base group by earlier computer modelling and the recent site directed mutagenesis studies. This study also implies that the 2'-deoxy-2'-fluoro substrate analog may not serve as a good model for determining the amino acid residue which serves as the general base group in ribonuclease catalysed reactions.

Binding Sites↗
PubMed1987

The effect of blood flow and diffusion impairment on pulmonary gas exchange: a computer model.

An assumption of the classical three-compartment lung model is that the physiologic shunt fraction (Qs/Qt) remains constant with changes in cardiac output (Qt). As a result, when Qt decreases, both the arterial O2 tension (PaO2) and the mixed venous O2 tension (PvO2) must also decrease. Yet observations in intact dogs with pulmonary edema and humans with the adult respiratory distress syndrome (ARDS) indicate that as Qt decreases, Qs/Qt occasionally declines while the PaO2 increases. The present study was conducted to examine these discordant observations using a computer model of pulmonary gas exchange with a diffusion impairment. A computer model of gas exchange was developed to specifically analyze the effect of changing Qt upon PaO2 and Qs/Qt in the presence of diffusion impairment. Using the classical three-compartment model of gas exchange, a diffusion impairment was inserted by a MIMIC subroutine. The results of this computer simulation indicated that in the presence of a diffusion impairment, lowering Qt caused PaO2 to increase while Qs/Qt and PvO2 decreased. These changes indicated that a diffusion impairment might account for the experimental observations of the effects of Qt on PaO2 in ARDS.

Cardiac Output↗
PubMed2006

A computational modelling study of oxygen vacancies at LaCoO3 perovskite surfaces.

Atomistic computational modelling of the surface structure of the catalytically-active perovskite LaCoO(3) has been undertaken in order to develop better models of the processes involved during catalytic oxidation processes. In particular, the energetics of creating oxygen ion vacancies at the surface have been investigated for the three low index faces (100), (110) and (111). Two mechanisms for vacancy creation have been considered involving dopant Sr(2+) cations at the La(3+) site and reduction of Co(3+) to Co(2+). For both mechanisms, there is a general tendency that the smaller the cation defect separation, the lower the energy of the cluster, as would be expected from simple electrostatic considerations. In addition, there are clear indications that oxygen vacancies are more easily created at the surface than in the bulk. The results also confirm that the presence of defects strongly influences crystal morphology and surface chemistry. The importance of individual crystal surfaces in catalysis is discussed in terms of the energetics for the creation of oxygen vacancies.

Binding Sites↗
PubMed2006

Computer modelling study of the mechanism of optic nerve injury in blunt trauma.

AIM: The potential causes of the optic nerve injury as a result of blunt object trauma, were investigated using a computer model. METHODS: A finite element model of the eye, the optic nerve, and the orbit with its content was constructed to simulate blunt object trauma. We used a model of the first phalanx of the index finger to represent the blunt body. The trauma was simulated by impacting the blunt body at the surface between the globe and the orbital wall at velocities between 2-5 m/s, and allowing it to penetrate 4-10 mm below the orbital rim. RESULTS: The impact caused rotations of the globe of up to 5000 degrees /s, lateral velocities of up to 1 m/s, and intraocular pressures (IOP) of over 300 mm Hg. The main stress concentration was observed at the insertion of the nerve into the sclera, at the side opposite to the impact. CONCLUSIONS: The results suggest that the most likely mechanisms of injury are rapid rotation and lateral translation of the globe, as well as a dramatic rise in the IOP. The strains calculated in the study should be sufficiently high to cause axonal damage and even the avulsion of the nerve. Finite element computer modelling has therefore provided important insights into a clinical scenario that cannot be replicated in human or animal experiments.

Computer Simulation↗
PubMed2002

Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties.

Classical concepts of atrial fibrillation (AF) have been rooted in Moe's multiple-wavelet hypothesis and simple cellular-automaton computer model. Recent experimental work has raised questions about the multiple-wavelet mechanism, suggesting a discrete "driver region" underlying AF. We reexplored the theoretical basis for AF with a 2-dimensional computer model of a 5x10-cm sheet of atrial cells with realistic ionic and coupling properties. Vagal actions were formulated based on patch-clamp studies of acetylcholine (ACh) effects. In control, a single extrastimulus resulted in a highly meandering unstable spiral wave. Simulated electrograms showed fibrillatory activity, with a dominant frequency (DF, 6.5 Hz) that correlated with the mean rate. Uniform ACh reduced core meander of the spiral wave by approximately 70% (as measured by the standard deviation of spiral-wave tip position) and accelerated the DF to 17.0 Hz. Simulated vagally induced refractoriness heterogeneity caused wavefront breakup as accelerated reentrant activity in regions of short refractoriness impinged on regions unable to respond in a 1:1 fashion because of longer refractoriness. In 7 simulations spanning the range of conditions giving sustained AF, 5 were maintained by single dominant spiral waves. On average, 3.0+/-1.3 wavelets were present (range, 1 to 7). Most wavelets were short-lived and did not contribute to AF maintenance. In contrast to predictions of the multiple-wavelet hypothesis, but in agreement with recent experimental evidence, our model indicates that AF can result from relatively stable primary spiral-wave generators and is significantly organized. Our results suggest that vagal AF may arise from ACh-induced stabilization of the primary spiral-wave generator and disorganization of the heterogeneous tissue response. The full text of this article is available at http://www.circresaha.org.

Acetylcholine↗