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PubMed2004

A computational model of auditory selective attention.

The human auditory system is able to separate acoustic mixtures in order to create a perceptual description of each sound source. It has been proposed that this is achieved by an auditory scene analysis (ASA) in which a mixture of sounds is parsed to give a number of perceptual streams, each of which describes a single sound source. It is widely assumed that ASA is a precursor of attentional mechanisms, which select a stream for attentional focus. However, recent studies suggest that attention plays a key role in the formation of auditory streams. Motivated by these findings, this paper presents a conceptual framework for auditory selective attention in which the formation of groups and streams is heavily influenced by conscious and subconscious attention. This framework is implemented as a computational model comprising a network of neural oscillators, which perform stream segregation on the basis of oscillatory correlation. Within the network, attentional interest is modeled as a Gaussian distribution in frequency. This determines the connection weights between oscillators and the attentional process, which is modeled as an attentional leaky integrator (ALI). Acoustic features are held to be the subject of attention if their oscillatory activity coincides temporally with a peak in the ALI activity. The output of the model is an "attentional stream," which encodes the frequency bands in the attentional focus at each epoch. The model successfully simulates a range of psychophysical phenomena.

Action Potentials↗
PubMed2000

Vocal fold bulging effects on phonation using a biophysical computer model.

Glottal adduction is a primary laryngeal variable that helps to determine glottal configuration and phonatory output. Greater adduction of the vocal folds can be produced by narrowing the gap between the vocal processes or by bulging the medial surface of the vocal folds. This study examined phonatory effects due to changing the degree of bulging using a computational model. Bulging was modeled as a quadratic surface and was related to active muscle stress. Results indicated that bulging had a significant effect on glottal flow resistance, maximum glottal width and area, and mean glottal volume velocity. The results are discussed relative to clinical issues of hyperfunction.

Biophysical Phenomena↗
PubMed2006

A computational model of how an interaction between the thalamocortical and thalamic reticular neurons transforms the low-frequency oscillations of the globus pallidus.

In Parkinson's disease, neurons of the internal segment of the globus pallidus (GPi) display the low-frequency tremor-related oscillations. These oscillatory activities are transmitted to the thalamic relay nuclei. Computer models of the interacting thalamocortical (TC) and thalamic reticular (RE) neurons were used to explore how the TC-RE network processes the low-frequency oscillations of the GPi neurons. The simulation results show that, by an interaction between the TC and RE neurons, the TC-RE network transforms a low-frequency oscillatory activity of the GPi neurons to a higher frequency of oscillatory activity of the TC neurons (the superharmonic frequency transformation). In addition to the interaction between the TC and RE neurons, the low-threshold calcium current in the RE and TC neurons and the hyperpolarization-activated cation current (I (h)) in the TC neurons have significant roles in the superharmonic frequency transformation property of the TC-RE network. The external globus pallidus (GPe) oscillatory activity, which is directly transmitted to the RE nucleus also displays a significant modulatory effect on the superharmonic frequency transformation property of the TC-RE network.

Action Potentials↗
PubMed1995

Computer modeling of adaptive depression.

Mild, delimited, and adaptive depression may be a specific example of a more general class of mechanism by which intelligent systems--individual, social, and artificial--adapt to dynamic, uncertain, and dangerous environments. Computer modeling, based on connectionist and artificial intelligence planning and learning programming techniques, supports this hypothesis by generating both adaptive behavior and analogs for 10 phenomena associated with depression: global, stable, and internal failure explantation, a cognitive loop of failure rumination, decreased motivation, self-esteem, and self-efficacy, and increased realism, negative generalization, and cognitive change. The idea of adaptive depression can be applied to more than one level of living systems. A better understanding of normal and adaptive depression may lead to a better understanding of clinical depression.

Adaptation, Psychological↗
PubMed1996

Computer modeling of 3D structures of cytochrome P450s.

The understanding of structure-function relationship of enzymes requires detailed information of their three-dimensional structure. Protein structure determination by X-ray and NMR methods, the two most frequently used experimental procedures, are often difficult and time-consuming. Thus computer modeling of protein structures has become an increasingly active and attractive option for obtaining predictive models of three-dimensional protein structures. Specifically, for the ubiquitous metabolizing heme proteins, the cytochrome P450s, the X-ray structures of four isozymes of bacterial origin, P450cam, P450terp, P450BM-3 and P450eryF have now been determined. However, attempts to obtain the structure of mammalian forms by experimental means have thus far not been successful. Thus, there have been numerous attempts to construct models of mammalian P450s using homology modeling methods in which the known structures have been used to various extents and in various strategies to build models of P450 isozymes. In this paper, we review these efforts and then describe a strategy for structure building and assessment of 3D models of P450s recently developed in our laboratory that corrects many of the weaknesses in the previous procedures. The results are 3D models that for the first time are stable to unconstrained molecular dynamics simulations. The use of this method is demonstrated by the construction and validation of a 3D model for rabbit liver microsomal P450 isozyme 2B4, responsible for the oxidative metabolism of diverse xenobiotics including widely used inhalation anesthetics. Using this 2B4 model, the substrate access channel, substrate binding site and plausible surface regions for binding with P450 redox partners were identified.

Amino Acid Sequence↗
PubMed1995

Block of impulse propagation at an abrupt tissue expansion: evaluation of the critical strand diameter in 2- and 3-dimensional computer models.

OBJECTIVE: Unidirectional conduction block in the heart can occur at a site where the impulse is transmitted from a small to a large tissue volume. The aim of this study was to evaluate the occurrence of conduction block in a 2-dimensional and 3-dimensional computer model of cardiac tissue consisting of a narrow strand abruptly emerging into a large area. In this structure, the strand diameter critical for the occurrence of block, hc, was evaluated as a function of changes in the active and passive electrical properties of both the strand and the large medium. METHODS: The effects of changes in the following parameters on hc were analysed: (1) maximum sodium conductance (gNamax), (2) longitudinal (Rx) and transverse (Ry) intracellular resistivities, and (3) inhomogeneities in gNamax and Rx and Ry between the strand and the large area. Three ionic models for cardiac excitation described by Beeler-Reuter, Ebihara-Johnson, and Luo-Rudy ionic current kinetics were compared. RESULTS: In the 2-dimensional simulations, hc was 175 microns in Ebihara-Johnson and Beeler-Reuter models and 200 microns in the Luo-Rudy model. At the critical strand diameter, the site of conduction block was located beyond the transition, i.e. a small circular area was activated in the large medium, whereas with narrower strands conduction block occurred within the strands. The decrease of gNamax resulted in a large increase of hc. This increase was mainly due to the change of gNamax in the large area, while hc was almost independent of gNamax in the strand. Changing Rx had no effect on hc, whereas the increase of Ry decreased hc and reversed conduction block. Inhomogeneous changes of Rx and Ry in the strand versus the large medium had opposite effects on hc. When the resistivities of the strand alone were increased, hc also increased. In contrast, the increase of the resistivities in the large area reduced hc. In the 3-dimensional model, hc was 2.7 times larger than the corresponding 2-dimensional values at the various levels of gNamax and resistivity. CONCLUSIONS: (1) At physiological values for active and passive electrical properties, hc in the 2D simulations is close to 200 microns in all three ionic models. In the 3-dimensional simulations, hc is 2.7 larger than in the 2-dimensional models. (2) The excitable properties of the large area but not of the strand modify hc. The decrease of intercellular coupling in the large medium facilitates impulse conduction and reduces hc, while the same change in the strand increases hc. (3) Occurrence of conduction block at an abrupt geometrical transition can be explained by both the impedance mismatch at the transition site and the critical curvature beyond the transition.

Animals↗
PubMed1999

Additive noise can enhance temporal coding in a computational model of analogue cochlear implant stimulation.

Conventional analogue multichannel cochlear implants are unlikely to convey formant information by the fine time structure of evoked discharges. Theoretically, however, the addition of noise to the channel outputs could enhance the representation of formants by time coding. In this study, the potential benefit of noise in analogue coding schemes was investigated using a computer model of cochlear implant stimulation. The cochlear nerve was modelled by the Frankenhauser-Huxley equations. For all five vowels investigated, the optimal addition of noise to the first channel of the simulated implant (200-671 Hz) caused enhancement of the first formant representation (as seen in amplitude spectra of the simulated discharges). For vowels with a low-frequency second formant, clear enhancement of the second formant resulted from the optimal addition of noise to the third channel (1200-2116 Hz). On the basis of the present computational study, additive noise would be expected to enhance the coding of temporal information by the discharges of a single nerve fiber.

Cochlear Implants↗
PubMed2001

Use of a computer model to identify potential hotspots for dengue fever in New Zealand.

AIMS: To describe the areas of potential dengue fever risk in New Zealand for present climatic conditions and projected scenarios of climate change. METHODS: A computer model, the HOTSPOTS System, was developed. This allowed the integration of climatic, topographical, entomological, demographic, trade and travel data to generate spatial information describing vector introduction risk, potential vector distribution and dengue fever risk. RESULTS: Under present climatic conditions, Auckland and Northland, and some coastal areas of other northern parts of the North Island, have a potential risk for dengue outbreaks supported by the vector Aedes albopictus. Greenhouse gas induced climate change could make these areas also receptive to Aedes aegypti--the more efficient tropical dengue vector--and increase the potential distribution of A. albopictus to much of the South Island. CONCLUSIONS: Given the introduction of a competent vector, there is an appreciable risk of dengue fever occurring in New Zealand under present climatic conditions. Greenhouse gas induced climate change would substantially increase the magnitude and spatial extent of this risk.

Climate↗
PubMed2002

Evaluating the dissolution behavior of zinc-complexed protein suspensions by computer modeling and simulation.

In vitro dissolution of zinc insulin suspensions can be promoted by the complexation of zinc with an ionic species for which the zinc ion has a greater affinity. Studies conducted by our group have previously shown that the rate-limiting steps that govern the dissolution of zinc-complexed insulin suspension may be (1) chemical complexation (surface reaction) and (2) subsequent drug mass transport (diffusion and solubility). The purpose of this work was to use a computer simulation model to predict the dissolution behavior of zinc-complexed insulin suspensions and determine the influence of the above rate-limiting steps on the overall process of dissolution. A quasi-steady-state model was chosen which included the effects of a shrinking particle radius, the drug's solubility, and a convective mass transfer term. Based on this model, the computer simulation program evaluated dissolution behaviors of various model drugs, including zinc insulin suspensions. The experimental data obtained from actual dissolution experiments were superimposed on computer-generated profiles that incorporated quantitative values to key terms, namely the alpha (diffusion resistance) and beta (surface reaction resistance) values. Results demonstrated that the computer simulations could be used to predict the dissolution behavior of zinc-complexed protein suspensions by manipulating the alpha and beta values. Overall, the computer simulations indicated the involvement of both the surface reaction and the diffusion rate-limiting steps in zinc insulin dissolution, which was consistent with the results obtained from actual experimental studies.

Computer Simulation↗
PubMed2005

Using OrgAhead, a computational modeling program, to improve patient care unit safety and quality outcomes.

As part of ongoing research to investigate the impact of patient characteristics, organization characteristics and patient unit characteristics on safety and quality outcomes, we used a computational modeling program, OrgAhead, to model patient care units' achievement of patient safety (medication errors and falls) and quality outcomes. We tuned OrgAhead using data we collected from 32 units in 12 hospitals in Arizona. Validation studies demonstrated acceptable levels of correspondence between actual and virtual patient units. In this paper, we report how we used OrgAhead to develop testable hypotheses about the kinds of innovations that nurse managers might realistically implement on their patient care units to improve quality and safety outcomes. Our focus was on unit-level innovations that are likely to be easier for managers to implement. For all but the highest performing unit (for which we encountered a ceiling effect), we were able to generate practical strategies that improved performance of the virtual units that could be implemented by actual units to improve safety and quality outcomes. Nurse managers have responded enthusiastically to the additional decision support for quality improvement.

Arizona↗
PubMed2002

Dynamics and interaction of filaments in a computational model of re-entrant ventricular fibrillation.

Ventricular fibrillation (VF) is a lethal cardiac arrhythmia. Re-entry, in which action potential wavefronts rotate around filaments, is believed to sustain VF. In this study we used a computational model of multiple wavelet fibrillation in the thin-walled right ventricle (10 mm thick) and the thicker walled left ventricle (16 mm thick) to investigate the effect of tissue thickness and initiation protocol on re-entry, and to examine whether filament dynamics and interaction in the model could explain why re-entry is both rarely observed and short-lived in experimental studies that map electrical activation on the heart surface. We found (i) that the density of filaments, the proportion of transmural filaments and the proportion of filaments visible on the model surface were all higher in the 10 mm simulation, (ii) that the initiation protocol influences the rate of filament breakdown but not the number of filaments present after 1 s, and (iii) that although many filaments are visible on the surface of the model, the majority are visible for less than one rotation. This study shows that tissue thickness, geometry and initiation protocol influence electrical activation during VF, and that the rapid motion and interaction of filaments result in transient appearance of surface re-entry.

Anisotropy↗
PubMed2004

Physiological basis of muscle functional MRI: predictions using a computer model.

Muscle functional MRI (mfMRI) has been proposed as a tool for noninvasively measuring the metabolic and hemodynamic responses to muscle activation, but its theoretical basis remains unclear. One challenge is that it is difficult to isolate individually those variables affecting the magnitude and temporal pattern of the mfMRI response. Therefore, the purpose of this study was to develop a computer model of how physiological factors altered during exercise affect the mfMRI signal intensity time course and then predict the contributions made by individual factors. A model muscle containing 39,204 fibers was defined. The fiber-type composition and neural activation strategies were designed to represent isometric contractions of the human anterior tibialis muscle, for which published mfMRI data exist. Sustained isometric contractions at 25 and 40% maximum voluntary contraction were modeled, as were the vascular (capillary recruitment, blood oxygen extraction) and metabolic (lactate accumulation, phosphocreatine hydrolysis, pH) responses. The effects on the transverse relaxation of MRI signal were estimated, and the mfMRI signal intensity time course was measured from simulated images. The model data agreed well qualitatively with published experimental data, and at long exercise durations the quantitative agreement was also good. The model was then used to predict that NMR relaxation effects secondary to blood volume and oxygenation changes, plus the creatine kinase reaction, dominate the mfMRI time course at short exercise durations (up to approximately 45 s) and that effects secondary to glycolysis are the main contributors at later times.

Animals↗
PubMed1997

Computer modeling of the effects of aortic valve stenosis and arterial system afterload on left ventricular hypertrophy.

The degree of left ventricular hypertrophy is generally thought to reflect the severity of aortic stenosis. However, the compounded influence of arterial system load is poorly understood. We developed a computer model to investigate the effects of aortic valve stenosis in combination with various systemic arterial parameters in the development of left ventricular hypertrophy. Data show that an increased peripheral resistance and/or aortic valve resistance, results in an increase in left ventricular wall thickness and mass, while peak systolic wall stress remains constant. Changing arterial compliance to above normal level would not induce significant changes in wall thickness, while reduction in arterial compliance below normal would cause an increase in ventricular wall thickness. When a double load is imposed on the left ventricle by way of a stenotic valve and an increased arterial afterload, a greater and an aggregated increase in wall thickness results, hastening the hypertrophic process.

Algorithms↗
PubMed2003

Velocity-driven adiabatic fast passage for arterial spin labeling: results from a computer model.

Velocity-driven adiabatic fast passage (AFP) is commonly employed for perfusion imaging by continuous arterial spin labeling (CASL). The degree of inversion of protons in blood determines the sensitivity of CASL to perfusion. For this study, a computer model of the modified Bloch equations was developed to establish the optimum conditions for velocity-driven AFP. Natural variations in blood velocity over the course of the cardiac cycle were found to result in significant variations in the degree of inversion. However, the mean degree of inversion was similar to that for blood moving at a constant velocity, equal to the time-averaged mean, at peak velocities and heart rates within normal ranges. A train of RF pulses instead of a continuous RF pulse for labeling was found to result in a highly nonlinear dependence of the degree of inversion on RF duty cycle. This may have serious implications for the quantification of perfusion.

Animals↗
PubMed1997

Effects of heart rate on vulnerability to fibrillation in a computer model.

Effects of heart rate on refractory period (RP) duration and disparity have opposing actions on vulnerability to fibrillation. Both bradycardia and tachycardia have been reported to increase vulnerability to fibrillation, and the role of their effects on RP duration and disparity in producing that effect is uncertain. That role has been investigated with a computer model of propagated excitation having nonuniform, cycle length-dependent refractoriness and slow propagation during incomplete recovery of excitability. Vulnerability was assessed as fibrillation threshold (FT), defined as the duration of train stimulation required to initiate simulated fibrillation. When measured as a function of train onset time during a cycle, FT initially decreased to a minimum and then increased to the original level. Slower rates shifted that curve upward and to the right, so that the FT was higher during early portions of the cycle but lower in later portions. Longer mean duration of RPs increased FT during all portions of the cycle, increased the difference of FT at various rates during early portions of the cycle, and decreased differences later in the cycle. Greater RP range reduced the FT and decreased the difference of FT with varied rate in early portions of the cycle, while increasing the difference in later portions. Accelerating rate had additional effects on FT-related to nonuniform propagation of responses prior to train stimulation. The findings defined mechanisms based on established effects of rate on RP, by which either tachycardia or bradycardia could increase vulnerability to fibrillation, and demonstrated the effects of RP range and duration on the mechanisms.

Atrial Fibrillation↗
PubMed1995

The adaptive significance of social synchronisation of ultradian behaviour cycles: a computer model.

Daily behaviour patterns in a hunter-gatherer community of Colombian Indians show that individual activities are regulated by ultradian behaviour cycles of about 2 hr and that these cycles can be synchronised by social interaction. A computer model was developed which simulated an artificial community and generated dynamic portraits of locomotor activity and social aggregation similar to those of the observed community of Colombian Indians. Social phase-locking of ultradian behaviour cycles occurred, contributing to the safety of group members and their economy of effort in gathering and related activities. Social synchronisation of ultradian behaviour cycles may also have occurred in early hominid groups.

Circadian Rhythm↗
PubMed1994

A physiologically based pharmacokinetic computer model for human pregnancy.

A physiologically based pharmacokinetic (PBPK) model for human pregnancy must incorporate many factors that are not usually encountered in PBPK models of mature animals. Models for pregnancy must include the large changes that take place in the mother, the placenta and the embryo/fetus over the period of pregnancy. The embryo/fetal weight change was modeled using the Gompertz equation for growth which gave a good fit to extensive pooled weight data of the human embryo/fetus from 25 to 300 days of gestation. This equation is based on a growth rate that is proportional to the total weight of the organism with the proportionality factor decreasing exponentially with time. Allometric equations, which are widely used to relate organ weights, blood flow rates and other attributes of mature animals to total weight, were adapted to correlate fetal organ weights with total fetal weight. Allometric relationships were also developed for plasma flow rates and other organ-related parameters. The computer model, written in FORTRAN 77, included 27 compartments for the mother and 16 for the fetus; it also accommodates two substances allowing representation of a parent compound and a metabolite (or a second drug or environmental substance). Although this model is large, the inherent sparsity in the equations allow it to be solved numerically in a reasonable time on currently available, reasonably priced desktop computers. A nonlinear regression routine is included to fit key model parameters to experimental data. Concentrations of chemicals administered and measured in the mother may be simulated in both maternal and fetal organs at any day(s) between 25 days and 300 days of gestation. Allometric relationships are also utilized to adopt this human model for use with data obtained from animal experiments.

Abnormalities, Drug-Induced↗