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PubMed2006

Modeling the sensitivity to variability relationship in perimetry.

PURPOSE: Studies in glaucoma patients show that standard automated perimetry results increase in variability as sensitivity decreases. However, the reasons for this change are unclear. This study presents the principle of Divergent Dysfunction as a possible explanation for this change in variability, and incorporates it into a model that can be used to simulate perimetry. METHODS: A computer program was written to simulate visual field test results based on the model, using a Full Threshold testing strategy. The validity of the simulation was tested by comparing it with normal sensitivity values, and with test-retest data from 63 participants evaluated five times each over the course of 1 month. The effect on the simulated data of varying parameters of the model was investigated, such as changing the magnitude of variability and the percentages of false positive and negative responses. RESULTS: The correlation between subject and simulated test-retest data was 0.987. Several factors were found to affect the sensitivity-variability relationship for the simulated data, most notably the rate of sensitivity decline, the percentage of false positives, and the starting luminance of the test procedure. CONCLUSIONS: The principle of Divergent Dysfunction presented here provides a plausible explanation for the sensitivity-variability relationship for standard automated perimetry in glaucomatous eyes. The model and resultant simulation program aim to provide an intuitive demonstration of the principle, which can also be used to examine the effectiveness of different testing strategies. These findings have great implications for future clinical research.

Computer Simulation↗

PubMed2002

Inner ear pathology in the mucopolysaccharidosis VII mouse.

Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is caused by dysfunction of the acid hydrolase beta-D-glucuronidase. The defect results in the accumulation of incompletely degraded glycosaminoglycans within lysosomes of a wide array of cell types. MPS VII is associated with mixed (conductive and sensorineural) hearing loss, vision defects, shortened stature, mental retardation and decreased lifespan. Whether the sensorineural component of hearing loss in MPS VII involves degeneration of cochlear sensory cells is not yet clear. The MPS VII mouse resembles its human counterpart in all major aspects, and has been the focus of extensive research seeking to correct MPS VII and other lysosomal storage diseases. The value of potential treatments for this hearing loss can be determined only if cochlear pathology in this model is well characterized. We examined threshold sensitivity, frequency tuning, hair cell density and the appearance of the cochlea and vestibular organs in MPS VII mice ranging from 1.0 to 7.5 months of age. At all ages, lysosomal storage is pronounced within cells of spiral limbus, spiral prominence, spiral ligament and glial cells, but not within organ of Corti, stria vascularis, or neurons. Within the vestibular maculae and cristae, both hair cells and supporting cells also show lysosomal storage. Although hearing thresholds are never normal, reduction in the sharpness of frequency tuning is not apparent until 2.5 months of age, suggesting that the sensorineural component of hearing loss begins in adulthood. No evidence was found for cell loss within the organ of Corti, or any other structure, however. Our results suggest that sensorineural hearing loss in the MPS VII mouse is not caused by degeneration, but may arise from alterations in mass and stiffness of cochlear structures or impaired sensory cell function. They also indicate a possible vestibular component in MPS VII.

Action Potentials↗

PubMed2005

Human vision fails to distinguish widespread sexual dichromatism among sexually "monochromatic" birds.

Historical scenarios of evolution of avian plumage coloration have been called into question with the discoveries that most birds can see UV light (which normal humans cannot), and that UV-reflecting plumages are widespread in birds. Several examples of sexual dichromatism not detectable with human visual capabilities suggest that our categorizations of plumages as sexually mono- or dichromatic might often be incorrect. Nonetheless, given the limited taxonomic scope of those examples, the vast majority of sexually monochromatic birds are still treated as such without question in avian research. Herein, I show that >90% of 139 species, in a broad sampling of presumed sexually monochromatic passerine birds, were actually sexually dichromatic from an avian visual perspective, based on comparisons of plumage reflectance data using a visual model of color discrimination thresholds. The taxonomic ubiquity of this result suggests that many existing interpretations of evolutionary patterns of sexual dichromatism in birds are erroneous. The visual model used herein provides a method for quantifying sexual dichromatism, revealing that most (58.7%) feather patches sampled lie along a continuum of dichromatism between avian and human discriminatory abilities and could represent unrecognized sexually selected signals. Sexual dichromatism in this study rarely resulted from intersexual differences in UV coloration alone, emphasizing the need for analysis of bird coloration in relation to the full extent of avian visual discriminatory abilities, including, but not limited to, UV-visual capabilities.

Animals↗

PubMed2004

Hearing aid accessories for adults: the remote FM microphone.

OBJECTIVE: The primary goal was to determine the benefits and limitations of a remote FM microphone as a hearing aid accessory. A secondary goal was to determine the predictors of aided and FM-assisted speech perception by adults with hearing loss, in quiet and in noise, using methods derived from Articulation Index theory. DESIGN: Twelve adults with mild to severe hearing loss, aged 52 to 85, were fit with behind-the-ear FM hearing aids and used them for a minimum of 2 wk. Phoneme recognition was measured before and after the trial period at several speech levels under three conditions: aided in quiet, aided in spectrally matched noise, and FM-assisted in noise. A single session of counseling, instruction and demonstration was provided before the trial period. Perceived benefit was assessed by questionnaire at the end of the trial period. Measured and perceived benefit were examined in relation to age and pure-tone thresholds. RESULTS: FM-assisted phoneme recognition in noise equaled aided phoneme recognition in quiet. Both were very well predicted by the average pure-tone threshold at 2 and 4 kHz, under a model that assumes Articulation Index (AI) falls with increasing high-frequency threshold at the rate of about 1 percentage point per dB. Aided phoneme recognition in noise was quite well predicted by the same average threshold, under a model that assumes a signal-to-noise ratio of 0 dB reduces Articulation Index to one third of that in quiet. Average perceived benefit was highest for one talker, at a distance, in quiet or in noise. It was lowest for multiple talkers (where the system would be expected to be ineffective) and one close talker in quiet (where the system should be unnecessary). Older subjects and subjects with poorer aided recognition in noise tended to express lower perceived benefit. Many subjects reported that the system was ineffective in reducing background noise. This finding was attributed to use of an "equal gain" criterion in adjusting relative gains via the hearing aid and FM microphones. The single pretrial session of counseling, instruction and demonstration was clearly inadequate for many of the subjects. None expressed an intention to acquire an FM system. CONCLUSIONS: The expected benefits of a remote FM microphone in reducing the negative effects of distance and noise, for a single talker, can be demonstrated under both laboratory and field conditions. The effects of hearing loss, noise and FM assistance, on aided phoneme recognition, are well predicted by methods derived from Articulation Index theory. Considerable counseling, instruction and coaching will be needed, however, to ensure optimal use of this technology. In addition, the relative gains via FM and hearing aid microphones must be adjusted with care.

Aged↗

PubMed2000

Elimination of spiral waves in cardiac tissue by multiple electrical shocks.

We study numerically the elimination of a spiral wave in cardiac tissue by application of multiple shocks of external current. To account for the effect of shocks we apply a recently developed theory for the interaction of the external current with cardiac tissue. We compare two possible feedback algorithms for timing of the shocks: a "local" feedback algorithm 11 (using an external electrode placed directly on the tissue) and a "global" feedback algorithm 22 (using the electrocardiogram). Our main results are: application of the external current causes a parametric resonant drift similar to that reported in previous model computations; the ratio of the threshold of elimination of the spiral wave by multiple shocks to the threshold of conventional single shock defibrillation in our model for cardiac tissue is about 0.5, while earlier, less realistic models predicted the value about 0.2; we show that an important factor for successful defibrillation is the location of the feedback electrode and the best results are achieved if the feedback electrode or the ECG lead is located at the boundary (or edge) of the cardiac tissue; the "local" and the "global" feedback algorithms show similar efficiency.

Algorithms↗

PubMed1993

Modeling of neural systems by use of neuronal modes.

A methodology for modeling spike-output neural systems from input-output data is proposed, which makes use of "neuronal modes" (NM) and "multi-input threshold" (MT) operators. The modeling concept of NM's was introduced in a previously published paper in order to provide concise and general mathematical representations of the nonlinear dynamics involved in signal transformation and coding by a class of neural systems. This paper presents and demonstrates (with computer simulations) a method by which the NM's are determined using the 1st- and 2nd-order kernel estimates of the system, obtained from input-output data. The MT operator (i.e., a binary operator with multiple real-valued operands which are the outputs of the NM's) possesses an intrinsic refractory mechanism and generates the sequence of output spikes. The spike-generating characteristics of the MT operator are determined by the "trigger regions" defined on the basis of data. This approach is offered as a reasonable compromise between modeling complexity and prediction accuracy, which may provide a common methodological framework for modeling a certain class of neural systems.

Computer Simulation↗

PubMed1999

Pharmacokinetics and pharmacodynamics of avitriptan during intravenous administration in healthy subjects.

Avitriptan, a selective 5-HT1-like receptor agonist, is an effective compound for the treatment of migraine headaches with a prolonged duration of response. A double-blind, placebo-controlled, parallel-group, ascending-dose study in 24 healthy subjects was designed to assess the safety, tolerance, pharmacokinetics, and pharmacodynamics of avitriptan. This antimigraine drug was administered as two consecutive constant-rate IV infusions at three dose levels (12.7, 25.3, and 38.0 mg), which were targeted to produce plasma concentrations in and above the therapeutic range. The best fitting of the plasma concentration-time data was obtained by using a triexponential function yielding a terminal t1/2 of 8 hours. The areas under the plasma concentration versus time curves were proportional to dose, indicating linear pharmacokinetics. Moreover, the clearance and steady-state volume of distribution values were independent of the dose. The change in pulse rate and supine systolic and diastolic blood pressure was determined as pharmacodynamic effects of avitriptan. A "threshold log-linear" model, which accounts for the linear increase in pharmacodynamic effect with the log of plasma concentrations when the latter was higher than a certain threshold value, adequately described the pharmacodynamic data. The threshold plasma drug concentrations for the pulse rate and the diastolic and systolic blood pressure were 14, 74, and 161 ng/ml, respectively. Overall, avitriptan has consistent, linear pharmacokinetics and increases systolic and diastolic blood pressure in a predictable manner at a higher plasma concentration. However, this drug does not produce a significant change in pulse rate at the dose levels (12.7-38 mg) evaluated in this study.

Adult↗

PubMed1976

Electrochemical neuron model.

1) A mathematical model for the behavior of passive iron in nitric acid, based on the electrochemical mechanisms, has been proposed. The model is capable of explaining several phenomena including threshold for activation, monostable property, periodic activation, propagation of activation, and threshold for propagation. Furthermore, the mathematical model predicts that the electrochemical active line has a specific propagated waveform and velocity of propagation. 2) By using iron-silver junctions in nitric acid, we could form a McCulloch-Pitts type neuron model. Also we could show the occurrence of reverberation on a net of iron wires in nitric acid.

Electrochemistry↗

PubMed1987

Computer simulation of fibrillation threshold measurements and electrophysiologic testing procedures.

A finite element model of cardiac conduction was used to simulate two experimental protocols: 1) fibrillation threshold measurements and 2) clinical electrophysiologic (EP) testing procedures. The model consisted of a cylindrical lattice whose properties were determined by four parameters: element length, conduction velocity, mean refractory period, and standard deviation of refractory periods. Different stimulation patterns were applied to the lattice under a given set of lattice parameter values and the response of the model was observed through a simulated electrocardiogram. The studies confirm that the model can account for observations made in experimental fibrillation threshold measurements and in clinical EP testing protocols.

Algorithms↗

PubMed1997

A psychoacoustic model for the noise masking of plosive bursts.

A model for predicting the masked thresholds of the voiceless plosive bursts /k,t,p/ in background noise is proposed. Because plosive bursts are brief, are generated by a noise source, and have different spectral characteristics, the modeling approach accounts for duration, center frequency, and signal bandwidth. Noise-in-noise masking experiments are conducted using a broadband masker and bandpass noise signals of varying bandwidth (100-5483 Hz), duration (10-300 ms), and center frequency (0.4-4 kHz). Data from these experiments are used to parametrize an auditory filter model in which the effective bandwidth and the signal-to-noise ratio at threshold for each filter are duration dependent. The duration-dependent filter model is then used to predict the thresholds of synthetic and naturally spoken plosive bursts in background noise. Finally, results from pilot notched-noise experiments are presented which support duration-dependent frequency selectivity.

Adult↗

PubMed2004

Spontaneous breathing through an inspiratory impedance threshold device augments cardiac index and stroke volume index in a pediatric porcine model of hemorrhagic hypovolemia.

BACKGROUND: Hemorrhagic shock secondary to trauma is associated with poor survival. The impedance threshold device (ITD) has been shown to improve blood pressure and survival rates in an adult porcine model of hemorrhagic hypovolemia. Pediatric hemodynamics, anatomy, and physiology differ from adults. Evaluation of the ITD has not been previously assessed in a pediatric porcine model of hypovolemia induced by hemorrhage. OBJECTIVE: To determine whether ITD-assisted breathing, with and without positive end-expiratory pressure, will improve key hemodynamic parameters following hypovolemia induced by hemorrhage in a pediatric porcine model. METHODS: Intubated, anesthetized, hemodynamically stable, spontaneously breathing piglets were rapidly bled 40% of their calculated blood volume. Piglets' hemodynamic and intrathoracic pressures were continuously monitored during 10-min normovolemic baseline, bleed to hypotensive baseline, 10-min ITD-assisted breathing, 10 mins without ITD, 10-min ITD-assisted breathing randomized with or without positive end-expiratory pressure (3 cm H2O), 10 mins without ITD, reinfusion of shed blood, 10-min baseline following return to normovolemia. The ITD had an inspiratory cracking pressure of -7 cm H2O. Transthoracic echocardiographic parameters were measured at the end of each 10-min period. RESULTS: There was no significant difference in baseline assessments between groups. Systolic blood pressure, cardiac index, and stroke volume index were significantly greater during ITD-assisted breathing. There was a trend toward increased left ventricular end-diastolic dimension during ITD use. Heart rate, systemic vascular resistance index, left ventricular end-systolic dimension, and shortening fraction did not change significantly during ITD-assisted breathing. There was equivalent improvement in systolic blood pressure, cardiac index, and stroke volume index, when the ITD alone and ITD plus positive end-expiratory pressure were used. CONCLUSIONS: ITD-assisted breathing significantly augmented systolic blood pressure, cardiac index, and stroke volume index in this pediatric porcine model of hemorrhagic hypovolemia. These effects appear related to increased left ventricular preload and not by increased systemic vascular resistance or heart rate. These beneficial effects of ITD-assisted breathing are not changed by the addition of positive end-expiratory pressures of 3 cm H2O.

Animals↗

PubMed2003

Wave bifurcation and propagation failure in a model of Ca(2+) release.

The De Young Keizer model for intracellular calcium oscillations is based around a detailed description of the dynamics for inositol trisphosphate (IP(3)) receptors. Systematic reductions of the kinetic schemes for IP(3) dynamics have proved especially fruitful in understanding the transition from excitable to oscillatory behaviour. With the inclusion of diffusive transport of calcium ions the model also supports wave propagation. The analysis of waves, even in reduced models, is typically only possible with the use of numerical bifurcation techniques. In this paper we review the travelling wave properties of the biophysical De Young Keizer model and show that much of its behaviour can be reproduced by a much simpler Fire-Diffuse-Fire (FDF) type model. The FDF model includes both a refractory process and an IP(3) dependent threshold. Parameters of the FDF model are constrained using a comprehensive numerical bifurcation analysis of solitary pulses and periodic waves in the De Young Keizer model. The linear stability of numerically constructed solution branches is calculated using pseudospectral techniques. The combination of numerical bifurcation and stability analysis also allows us to highlight the mechanisms that give rise to propagation failure. Moreover, a kinematic theory of wave propagation, based around numerically computed dispersion curves is used to predict waves which connect periodic orbits. Direct numerical simulations of the De Young Keizer model confirm this prediction. Corresponding travelling wave solutions of the FDF model are obtained analytically and are shown to be in good qualitative agreement with those of the De Young Keizer model. Moreover, the FDF model may be naturally extended to include the discrete nature of calcium stores within a cell, without the loss of analytical tractability. By considering calcium stores as idealised point sources we are able to explicitly construct solutions of the FDF model that correspond to saltatory periodic travelling waves.

Algorithms↗

PubMed1988

Associative neural network model for the generation of temporal patterns. Theory and application to central pattern generators.

Cyclic patterns of motor neuron activity are involved in the production of many rhythmic movements, such as walking, swimming, and scratching. These movements are controlled by neural circuits referred to as central pattern generators (CPGs). Some of these circuits function in the absence of both internal pacemakers and external feedback. We describe an associative neural network model whose dynamic behavior is similar to that of CPGs. The theory predicts the strength of all possible connections between pairs of neurons on the basis of the outputs of the CPG. It also allows the mean operating levels of the neurons to be deduced from the measured synaptic strengths between the pairs of neurons. We apply our theory to the CPG controlling escape swimming in the mollusk Tritonia diomedea. The basic rhythmic behavior is shown to be consistent with a simplified model that approximates neurons as threshold units and slow synaptic responses as elementary time delays. The model we describe may have relevance to other fixed action behaviors, as well as to the learning, recall, and recognition of temporally ordered information.

Animals↗

PubMed1999

Cone signal contributions to electroretinograms [correction of electrograms] in dichromats and trichromats.

PURPOSE: To find out how the different cone types contribute to the electroretinogram (ERG) by quantifying the contribution of the signal pathways originating in the long (L-) and the middle (M-) wavelength-sensitive cones to the total ERG response amplitude and phase. METHODS: ERG response amplitudes and phases were measured to cone-isolating stimuli and to different combinations of L- and M-cone modulation. Conditions were chosen to exclude any contribution of the short wavelength-sensitive (S-) cones. The sensitivity of the ERG to the L and the M cones was defined as the cone contrast gain. RESULTS: In the present paper, a model is provided that describes the ERG contrast gains and ERG thresholds in dichromats and color normal trichromats. For the X-chromosome-linked dichromats, the contrast gains of only one cone type (either the L or the M cones) sufficed to describe the ERG thresholds for all stimulus conditions. Data suggest that the M-cone contrast gains of protanopes are larger than the L-cone contrast gains of deuteranopes. The response thresholds of the trichromats are modeled by assuming a vector summation of signals originating in the L and the M cones. Their L- and M-cone contrast gains are close to a linear interpolation of the data obtained from the dichromats. Nearly all trichromats had larger L- than M-cone contrast gains. Data from a large population of trichromats were examined to study the individual variations in cone weightings and in the phases of the cone pathway responses. CONCLUSIONS: The data strongly suggest that the missing cone type in dichromats is replaced by the remaining cone type. The mean L-cone to M-cone weighting ratio in trichromats was found to be approximately 4:1. But there is a substantial interindividual variability between trichromats. The response phases of the L- and the M-cone pathways can be reliably quantified using the response phases to the cone-isolating stimuli or using a vector addition of L- and M-cone signals.

Adolescent↗

PubMed1980

Morphogenetic properties of the skin in axolotl limb regeneration.

A study has been made of the morphogenetic properties of anterior and posterior skin from the lower forelimb of the axolotl. The basic experiment consisted of a graft of a half cuff of skin from a donor to a host limb followed by a 2-week healing period, amputation through the graft, and a study of the resulting regenerate. Limbs with double posterior skin formed double posterior regenerates and, in contrast, limbs with double anterior skin formed normal or slightly hypomorphic regenerates. Posterior skin from post-metamorphic animals had a similar but weaker effect to that from ordinary axolotls. Immunological rejection of allografts could be completely avoided if the donor limb was transplanted to the flank of the host when both were at the stage of tail-bud embryos, and the skin graft was later carried out between the supernumerary limb and one of the host limbs. This technique was used to show that immunological rejection does not affect the formation of duplicates from the limbs with double posterior skin, and to facilitate the studies of the cellular provenance of the regenerate. The cellular composition of duplicate regenerates was studied by using both triploid donors and triploid hosts. It was shown that the posterior side of the duplications consisted wholly of host tissue and the anterior side consisted of mixed donor and host tissue. Formation of the duplicated regenerate therefore seems to involve positional reprogramming of both donor and host tissues together with metaplasia of the donor tissue. It was not possible to inhibit the duplication-inducing property of posterior skin by treatment with a variety of enzymes. A model based on the serial threshold theory of regeneration is advanced to explain the results. This model successfully accounts for the observed non-equivalence of anterior and posterior skin, and also explains the different regeneration behaviour of anterior and posterior half limbs, the limited regeneration of double anterior limbs, and the pattern expansion and contraction shown by regenerates from double posterior limbs.

Ambystoma↗

PubMed2004

Genetic analysis of male and female fertility using longitudinal binary data.

A longitudinal Bayesian threshold analysis of insemination events during the first 250 d after calving of first-parity Holsteins was carried out. The outcome of an insemination event was treated as a binary response of either a success (1) or a failure (0). Thus, all breeding information for a cow, including all service sires, was included, thereby allowing for a joint evaluation of male and female fertility. An edited data set of 297,823 insemination records from 151,758 first lactation cows was used. On the liability scale, the model included the systematic effects of herd-year of insemination, technician, month of insemination, and regressions on age of service sire, 3 test days in the first 100 d of lactation (early milk yield), and days in milk at insemination. The random effects in the model were the additive breeding value, the permanent effect of the cow, and the service sire effect. Posterior mean (standard deviation) of the dispersion parameters in the model were 0.034 (0.006), 0.009 (0.001), and 0.171 (0.013) for the additive, service sire, and permanent environmental variances, respectively. The residual variance was fixed at 1, as a result of the nonidentifiability of the threshold model. The posterior mean (standard deviation) of heritability was 0.028 (0.005). This point estimate of heritability is well within the range of available estimates for the trait. Thus, these estimates suggest that some genetic variation exists that can potentially be used to improve reproductive performance or at least avoid its further deterioration. The estimate of the regression coefficient on age of service sire was 0.001, indicating better fertility among older bulls. However, this result has to be interpreted with caution given the preferential use of proven bulls on well-managed cows (as opposed to problem breeders). The estimate of the regression coefficient was negative (-0.005) for early milk yield, as expected, and positive (0.003) for days in milk at insemination. This suggests that high-producing cows are less likely to conceive at the beginning of lactation.

Age Factors↗

PubMed1999

Steroid-responsive cochlear dysfunction in the MRL/lpr autoimmune mouse.

Corticosteroids historically have been used to treat autoimmune sensorineural hearing loss, although little is known of how steroids restore normal inner ear function. Therefore, to identify a potential model for this field of research, this study examined the effects of prednisolone on auditory brain stem response thresholds in the MRL/lpr mouse model of autoimmune sensorineural hearing loss. Mice treated with prednisolone after auditory threshold elevations demonstrated significant improvement and stabilization of thresholds compared with untreated controls. MRL/lpr mice treated with steroids before the onset of autoimmune disease and cochlear dysfunction demonstrated decreased serum immune complexes, higher survival rates, and lower auditory thresholds compared with untreated controls. These positive results suggest the autoimmune mouse may be useful for studies of steroid-responsive mechanisms of the cochlea in autoimmune sensorineural hearing loss, as well as any hearing disorder in which steroid therapy is currently used.

Animals↗

PubMed1995

Quantifying 2-factor phase relations in non-linear responses from low characteristic-frequency auditory-nerve fibers.

Auditory-nerve excitation by two response factors that can be in antiphase has been hypothesized by Kiang (1990) on the basis of non-linear interference in responses to tones (Kiang et al., 1969). The general conditions for antiphasic responses and the relevance of the hypothesis for other auditory stimuli are unknown. Clarification was sought in a systematic modeling study of published data on level-dependent non-linear responses from low characteristic-frequency (CF) auditory-nerve fibers for a broad variety of acoustic stimuli. The MBPNL non-linear I/O model of cochlear frequency analysis (Goldstein, 1990), which incorporates the 2-factor hypothesis, was used to simulate the reported non-linear phenomena. It was found that experiments with paired click stimuli (Goblick and Pfeiffer, 1969) and with octave-band complex tones (Horst et al., 1990), in addition to experiments with single clicks or tones, are sensitive to the phase difference between factors. Surprisingly, the paired-click transient responses require a quadrature phase, while the complex-tone steady-state responses require an antiphase relation. The MBPNL model simulations of all low-CF data surveyed,for simple and complex stimuli, are consistent with a quadrature phase for transient responses and antiphase relation for steady-state responses. It is hypothesized that some adaptive, low-CF, cochlear mechanism, not described by the basic MBPNL model, produces a temporal transition of the '2-factor' response from an initial quadrature relation (tip leading) to a final antiphase relation. New experimental and modeling research guided by this working hypothesis is proposed.

Acoustic Stimulation↗