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A four-compartment model is presented that simulates inorganic mercury [Hg(II)] pharmacokinetics in blood, tissue, and excreta over a 70-day period. Simulations are validated against data collected from five human subjects, and previously analyzed. In the model, two compartments simulate Hg(II) in blood: one for mobile-Hg(II) and the other for immobile-Hg(II). Two corresponding compartments simulate Hg(II) in tissue. Mobile-Hg(II) represents Hg(II) available for transport across cell membranes. Immobile-Hg(II) represents Hg(II) that is not easily transported. Following dosing, blood total-Hg(II) droped rapidly in all subjects. Blood mobile-Hg(II) also droped rapidly with a concomitant rise in blood immobile-Hg(II). For four subjects, immobile-Hg(II) became the dominant Hg(II) species in blood by day 4. For subject five, mobile-Hg(II) remained dominant in blood for the study duration. Tissue mobile-Hg(II) declined rapidly for four of the subjects, with a simultaneous rapid rise in tissue immobile-Hg(II). In subject 5, tissue mobile-Hg(II) declined linearly, and immobile-Hg(II) accumulated slowly in tissue. For all subjects, tissue mobile-Hg(II) is the primary source of fecal Hg(II). The major source for Hg(II) excreted into the urine is immobile-Hg(II) from tissue. [ABSTRACT FROM AUTHOR]

Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

The purpose of this study was to examine the agreement between body fat percentage (%Fat) estimates derived from a standardized ultrasound protocol (%FatIASMS), a commonly used skinfold (SKF)‐site‐based ultrasound protocol (%FatJP), and a criterion four‐compartment (4C) model (%Fat4C). For the ultrasound protocols, all measurement sites were marked, measured and analyzed by the same evaluator. Subcutaneous adipose tissue (SAT) thickness was measured manually at the region where the muscle fascia was parallel to the skin and the average value per measurement site was used to calculate body density and subsequently %Fat. A repeated‐measures analysis of variance with a priori planned contrasts was used to compare %Fat values between the 4C criterion and both ultrasound methods. Small nonsignificant mean differences were observed between %FatIASMS (18.82 ± 14.21%Fat, effect size [ES] = 0.25, p = 0.178), %FatJP (18.23 ± 13.32%Fat, ES = 0.32, p = 0.050) and the %Fat4C criterion (21.70 ± 7.57%Fat); however, %FatIASMS did not yield a smaller mean difference than the %FatJP (p = 0.287). Additionally, %FatIASMS (r = 0.90, p < 0.001, standard error of the estimate [SEE] = 3.29%) and %FatJP (r = 0.88, p < 0.001, SEE = 3.60%) were strongly correlated with the 4C criterion, however, %FatIASMS did not yield better agreement than %FatJP (p = 0.257). Despite slightly underestimating %Fat, both ultrasound techniques demonstrated Good—Very Good agreement with the 4C criterion, with comparable mean differences, correlations, and SEE. The International Association of Sciences in Medicine and Sports (IASMS) standardized protocol using manual calculations of SAT was comparable to the SKF‐site‐based ultrasound protocol when compared to the 4C criterion. These results indicate that the IASMS (with manually measured SAT) and SKF‐site‐based ultrasound protocols may be of practical use to clinicians. [ABSTRACT FROM AUTHOR]

Simple Summary: Perilesional T2 hyperintensity in glioblastomas and brain metastases shows neuropathologically detectable differences in the extent of edema formation. We compared novel diffusion microstructure imaging (DMI) with the more established NODDI and DTI techniques to determine if they could detect differences in free water content. Using DMI V-CSF and DTI MD, we found significant differences between glioblastomas and brain metastases in this regard but not with NODDI V-ISO. Although the free water content within the perilesional T2 hyperintense region should differ between glioblastomas (GBM) and brain metastases based on histological differences, the application of classical MR diffusion models has led to inconsistent results regarding the differentiation between these two entities. Whereas diffusion tensor imaging (DTI) considers the voxel as a single compartment, multicompartment approaches such as neurite orientation dispersion and density imaging (NODDI) or the recently introduced diffusion microstructure imaging (DMI) allow for the calculation of the relative proportions of intra- and extra-axonal and also free water compartments in brain tissue. We investigate the potential of water-sensitive DTI, NODDI and DMI metrics to detect differences in free water content of the perilesional T2 hyperintense area between histopathologically confirmed GBM and brain metastases. Respective diffusion metrics most susceptible to alterations in the free water content (MD, V-ISO, V-CSF) were extracted from T2 hyperintense perilesional areas, normalized and compared in 24 patients with GBM and 25 with brain metastases. DTI MD was significantly increased in metastases (p = 0.006) compared to GBM, which was corroborated by an increased DMI V-CSF (p = 0.001), while the NODDI-derived ISO-VF showed only trend level increase in metastases not reaching significance (p = 0.060). In conclusion, diffusion MRI metrics are able to detect subtle differences in the free water content of perilesional T2 hyperintense areas in GBM and metastases, whereas DMI seems to be superior to DTI and NODDI. [ABSTRACT FROM AUTHOR]

In vitro studies have shown that hippocampal pyramidal neurons employ a mechanism similar to stochastic resonance (SR) to enhance the detection and transmission of weak stimuli generated at distal synapses. To support the experimental findings from the perspective of multicompartment model analysis, this paper aimed to elucidate the phenomenon of SR in a noisy two-compartment hippocampal pyramidal neuron model, which was a variant of the Pinsky-Rinzel neuron model with smooth activation functions and a hyperpolarization-activated cation current. With a bifurcation analysis of the model, we demonstrated the underlying dynamical structure responsible for the occurrence of SR. Furthermore, using a stochastically generated biphasic pulse train and broadband noise generated by the Orenstein-Uhlenbeck process as noise perturbation, both SR and suprathreshold SR were observed and quantified. Spectral analysis revealed that the distribution of spectral power under noise perturbations, in addition to inherent neurodynamics, is the main factor affecting SR behavior. The research results suggested that noise enhances the transmission of weak stimuli associated with elongated dendritic structures of hippocampal pyramidal neurons, thereby providing support for related laboratory findings. [ABSTRACT FROM AUTHOR]

Abstract Background There is a need for new approaches to increase the knowledge of the membrane excitability of small nerve fibers both in healthy subjects, as well as during pathological conditions. Our research group has previously developed the perception threshold tracking technique to indirectly assess the membrane properties of peripheral small nerve fibers. In the current study, a new approach for studying membrane excitability by cooling small fibers, simultaneously with applying a slowly increasing electrical stimulation current, is evaluated. The first objective was to examine whether altered excitability during cooling could be detected by the perception threshold tracking technique. The second objective was to computationally model the underlying ionic current that could be responsible for cold induced alteration of small fiber excitability. The third objective was to evaluate whether computational modelling of cooling and electrical simulation can be used to generate hypotheses of ionic current changes in small fiber neuropathy. Results The excitability of the small fibers was assessed by the perception threshold tracking technique for the two temperature conditions, 20 °C and 32 °C. A detailed multi-compartment model was developed, including the ionic currents: NaTTXs, NaTTXr, NaP, KDr, KM, KLeak, KA, and Na/K-ATPase. The perception thresholds for the two long duration pulses (50 and 100 ms) were reduced when the skin temperature was lowered from 32 to 20 °C (p

Background and Aims: Measurement of body composition using computed tomography (CT) scans may be a viable clinical tool for low muscle mass assessment in oncology. However, longitudinal assessments are often infeasible with CT. Clinically accessible body composition technologies can be used to track changes in fat-free mass (FFM) or muscle, though their accuracy may be impacted by cancer-related physiological changes. The purpose of this study was to examine the agreement among accessible body composition method with criterion methods for measures of whole-body FFM measurements and, when possible, muscle mass for the classification of low muscle in patients with cancer., Methods: Patients with colorectal cancer were recruited to complete measures of whole-body DXA, air displacement plethysmography (ADP), and bioelectrical impedance analysis (BIA). These measures were used alone, or in combination to construct the criterion multicompartment (4C) mode for estimating FFM. Patients also underwent abdominal CT scans as part of routine clinical assessment. Agreement of each method with 4C model was analyzed using mean constant error (CE = criterion - alternative), linear regression including root mean square error (RMSE), Bland-Altman limits of agreement (LoA) and mean percentage difference (MPD). Additionally, appendicular lean soft tissue index (ALSTI) measured by DXA and predicted by CT were compared for the absolute agreement, while the ALSTI values and skeletal muscle index by CT were assessed for agreement on the classification of low muscle mass., Results: Forty-five patients received all measures for the 4C model and 25 had measures within proximity of clinical CT measures. Compared to 4C, DXA outperformed ADP and BIA by showing the strongest overall agreement (CE = 1.96 kg, RMSE = 2.45 kg, MPD = 98.15 ± 2.38%), supporting its use for body composition assessment in patients with cancer. However, CT cutoffs for skeletal muscle index or CT-estimated ALSTI were lower than DXA ALSTI (average 1.0 ± 1.2 kg/m 2 ) with 24.0% to 32.0% of patients having a different low muscle classification by CT when compared to DXA., Conclusions: Despite discrepancies between clinical body composition assessment and the criterion multicompartment model, DXA demonstrates the strongest agreement with 4C. Disagreement between DXA and CT for low muscle mass classification prompts further evaluation of the measures and cutoffs used with each technique. Multicompartment models may enhance our understanding of body composition variations at the individual patient level and improve the applicability of clinically accessible technologies for classification and monitoring change over time., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carla M Prado reports financial support was provided by Alberta Government. Katherine Ford reports a relationship with Abbott Nutrition that includes: consulting or advisory and paid expert testimony. Maria Cristina Gonzalez reports a relationship with Abbott Nutrition that includes: consulting or advisory. Carla M Prado reports a relationship with Abbott Nutrition that includes: consulting or advisory. Maria Cristina Gonzalez reports a relationship with Nutricia Research BV that includes: consulting or advisory. Maria Cristina Gonzalez reports a relationship with Nestle Brazil that includes: consulting or advisory. Carla M Prado reports a relationship with Nutricia Research BV that includes: consulting or advisory. Crala M Prado reports a relationship with Nestle Health Science that includes: consulting or advisory. Crala M Prado reports a relationship with AMRA medical that includes: consulting or advisory. Carla M Prado reports a relationship with Pfizer that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to compare body mass index (BMI)-based body fat percentage (BF%) equations and skinfolds with a 4-compartment (4C) model in men and women. One hundred thirty adults (63 women and 67 men) volunteered to participate (age = 23 ± 5 years). BMI was calculated as weight (kg) divided by height squared (m²). BF% was predicted with the BMI-based equations of Jackson et al. (BMIJA), Deurenberg et al. (BMIDE), Gallagher et al. (BMIGA), Zanovec et al. (BMIZA), Womersley and Durnin (BMIWO), and from 7-site skinfolds using the generalized skinfold equation of Jackson et al. (SF7JP). The 4C model BF% was the criterion and derived from underwater weighing for body volume, dual-energy X-ray absorptiometry for bone mineral content, and bioimpedance spectroscopy for total body water. The constant error (CE) was not significantly different for BMIZA compared with the 4C model (p = 0.74, CE = -0.2%). However, BMIJA, BMIDE, BMIGA, and BMIWO produced significantly higher mean values than the 4C model (all p < 0.001, CEs = 1.8-3.2%), whereas SF7JP was significantly lower (p < 0.001, CE = -4.8%). The standard error of estimate ranged from 3.4 (SF7JP) to 6.4% (BMIJA) while the total error varied from 6.0 (SF7JP) to 7.3% (BMIJA). The 95% limits of agreement were the smallest for SF7JP (±7.2%) and widest for BMIJA (±13.5%). Although the BMI-based equations produced similar group mean values as the 4C model, SF7JP produced the smallest individual errors. Therefore, SF7JP is recommended over the BMI-based equations, but practitioners should consider the associated CE. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare underwater weighing (UWW) and 4-compartment (4C) model body fat percentage (BF%) for predicted vs. simultaneously measured residual lung volume (RLV). Forty-seven women and 33 men (age = 22 ± 5 years) had UWW and 4C model BF% determined using Boren et al. (RLVBOREN), Goldman and Becklake (RLVGB), and Miller et al. (RLVMILLER) RLV prediction equations. Criterion UWW BF% included body density (BD) values with simultaneous RLV. Criterion 4C model BF% included BD through UWW with simultaneous RLV, total body water through bioimpedance spectroscopy, and bone mineral content through dual-energy x-ray absorptiometry. The standard error of estimate (SEE) for UWW and 4C model BF% determined through RLV prediction equations varied from 2.0 to 2.6% and from 1.3 to 1.5%, respectively. The constant error (CE) was significantly different for UWW BF% when using RLVBOREN, RLVGB, and RLVMILLER (all p < 0.016; CE = 0.7, -2.0, 1.0%, respectively). However, the CEs for RLVBOREN and RLVMILLER were not significant in the 4C model (p = 0.73 and 0.11; CE = 0.1 and 0.2%, respectively), whereas RLVGB remained significantly different (p < 0.001; CE = -1.5%). The 95% limits of agreement were less than ±5.2% for UWW BF% and less than ±3.1% for the 4C model when using the 3 RLV equations. When used in a 4C model, the RLV equations yielded a smaller CE, SEE, and 95% limits of agreement than UWW BF% results. However, because of the range of individual error shown in the current study, caution should be employed when using the 4C model as a criterion method with predicted RLV. [ABSTRACT FROM AUTHOR]

Objective The purpose of this investigation was to (i) assess the test-retest reliability and minimum difference (MD) values of air-displacement plethysmography (ADP) and the Siri 3-compartment (3-C) model in a mobile trailer, and (ii) identify any environmental fluctuations in the trailer. Methods percent body fat (%BF) was examined in 22 firefighters on two separate days in a climate-controlled mobile trailer using ADP. Total body water was examined in a subset of participants ( n = 12) using bioelectrical impedance spectroscopy (BIS) to determine %BF using Siri's 3-C model. Results There were no differences in environmental measures ( P≥0·138), %BF for ADP ( P = 0·276), or %BF for the Siri 3-C model ( P = 0·382) between day 1 and day 2. Intraclass correlation coefficient and standard error of measurement values for ADP and the Siri 3-C model were 0·978 and 1·3% and 0·986 and 0·6%, respectively. The MD values were 3·6% and 1·7%, respectively. Conclusions These findings indicate that ADP can reliably determine %BF when transported in a climate-controlled mobile trailer. Additional accuracy is achievable with the Siri 3-C model, providing an attractive and promising method to measure body composition in larger scale community-based settings. [ABSTRACT FROM AUTHOR]

Background New, silicon-based multielectrodes comprising hundreds or more electrode contacts offer the possibility to record spike trains from thousands of neurons simultaneously. This potential cannot be realized unless accurate, reliable automated methods for spike sorting are developed, in turn requiring benchmarking data sets with known ground-truth spike times. New method We here present a general simulation tool for computing benchmarking data for evaluation of spike-sorting algorithms entitled ViSAPy (Virtual Spiking Activity in Python) . The tool is based on a well-established biophysical forward-modeling scheme and is implemented as a Python package built on top of the neuronal simulator NEURON and the Python tool LFPy . Results ViSAPy allows for arbitrary combinations of multicompartmental neuron models and geometries of recording multielectrodes. Three example benchmarking data sets are generated, i.e., tetrode and polytrode data mimicking in vivo cortical recordings and microelectrode array (MEA) recordings of in vitro activity in salamander retinas. The synthesized example benchmarking data mimics salient features of typical experimental recordings, for example, spike waveforms depending on interspike interval. Comparison with existing methods ViSAPy goes beyond existing methods as it includes biologically realistic model noise, synaptic activation by recurrent spiking networks, finite-sized electrode contacts, and allows for inhomogeneous electrical conductivities. ViSAPy is optimized to allow for generation of long time series of benchmarking data, spanning minutes of biological time, by parallel execution on multi-core computers. Conclusion ViSAPy is an open-ended tool as it can be generalized to produce benchmarking data or arbitrary recording-electrode geometries and with various levels of complexity. [ABSTRACT FROM AUTHOR]

Objectives: Bone scintigraphy is reported to be useful for detecting bisphosphonate-related osteonecrosis of the jaw (BRONJ). In this clinical study, we employed a mathematical analysis of dynamic bone scintigraphy to evaluate bone disorders in BRONJ. Osteomyelitis (OM) and osteoradionecrosis (ORN) were analyzed for comparison. Methods: Forty patients who underwent bone scintigraphy with Tc-labeled hydroxymethylene diphosphonate (Tc HMDP) for diagnosis of bone disorders were entered into the study. The patients comprised 6 BRONJ patients, 6 ORN patients, and 28 mandibular OM patients; 90 normal control subjects without any bone diseases of the jaw were enrolled for comparison. The observed time-activity data for Tc in regions of interest were fitted to a multicompartment model. K and λ ratios reflecting bone blood flow and regional bone metabolism, respectively, were calculated. The ratios of affected disease side to normal side were obtained. Results: The K-ratios (mean ± SD) were 1.25 ± 0.15 in BRONJ, 1.20 ± 0.19 in OM, 1.09 ± 0.11 in ORN, and 0.99 ± 0.04 in normal subjects. The λ-ratios were 1.84 ± 0.45 in BRONJ, 2.37 ± 0.73 in OM, 1.52 ± 0.34 in ORN, and 1.03 ± 0.10 in normal subjects. The K-ratio in BRONJ was significantly higher than that in normal subjects, but did not differ from that in OM. The λ-ratio in BRONJ was low compared with OM, but increased compared with normal subjects. There were similarities in both ratios between BRONJ and ORN. Conclusions: Dynamic analyses using a multicompartment model may help toward understanding and evaluation of bone disorders in BRONJ. [ABSTRACT FROM AUTHOR]

The mechanical properties of the respiratory system are important determinants of its function and can be severely compromised in disease. The assessment of respiratory system mechanical properties is thus essential in the management of some disorders as well as in the evaluation of respiratory system adaptations in response to an acute or chronic process. Most often, lungs and chest wall are treated as a linear dynamic system that can be expressed with differential equations, allowing determination of the system's parameters, which will reflect the mechanical properties. However, different models that encompass nonlinear characteristics and also multicompartments have been used in several approaches and most specifically in mechanically ventilated patients with acute lung injury. Additionally, the input impedance over a range of frequencies can be assessed with a convenient excitation method allowing the identification of the mechanical characteristics of the central and peripheral airways as well as lung periphery impedance. With the evolution of computational power, the airway pressure and flow can be recorded and stored for hours, and hence continuous monitoring of the respiratory system mechanical properties is already available in some mechanical ventilators. This review aims to describe some of the most frequently used models for the assessment of the respiratory system mechanical properties in both time and frequency domain. [ABSTRACT FROM AUTHOR]

Microelectrodes placed within the densely packed cortical neuronal region are surrounded by many thin processes. Although dendrites are considered to be functionally different to axons, they also possess voltage sensitive membrane channels. Therefore, dendritic regions are suitable candidates for spike initiation sites when stimulated externally, although they demand two to three times higher thresholds in comparison with thin axons. Simulations based upon recently reported distributions of two types of sodium channels and traced pyramidal cell data accompanied by a simplified model structure enlightened the spike initiation sites for extracellular cortical microstimulation and revealed insights into dendritic excitation patterns. Surprisingly low dendritic threshold values for cathodic stimulation were detected, that is, 3.3 µA for a 0.4-µm diameter fiber excited with a 100-µs pulse in 4-µm distance. However, according to the activating function concept the excited region is calculated by 1414*electrode-distance, therefore a minimum electrode-fiber distance is required as sufficient sodium channels are needed to produce enough intracellular current for spike conduction. The minimum distance for dendritic spike initiation increases with diameter and hinders low current stimulation of thick dendrites. This effect is in contrast to the inverse recruitment order known from functional electrical stimulation. Simulations were performed using NEURON and MATLAB. [ABSTRACT FROM AUTHOR]

We investigate metabolic interactions between astrocytes and GABAergic neurons at steady states corresponding to different activity levels using a six-compartment model and a new methodology based on Bayesian statistics. Many questions about the energetics of inhibition are still waiting for definite answers, including the role of glutamine and lactate effluxed by astrocytes as precursors for γ-aminobutyric acid (GABA), and whether metabolic coupling applies to the inhibitory neurotransmitter GABA. Our identification and quantification of metabolic pathways describing the interaction between GABAergic neurons and astrocytes in connection with the release of GABA makes a contribution to this important problem. Lactate released by astrocytes and its neuronal uptake is found to be coupled with neuronal activity, unlike glucose consumption, suggesting that in astrocytes, the metabolism of GABA does not require increased glycolytic activity. Negligible glutamine trafficking between the two cell types at steady state questions glutamine as a precursor of GABA, not excluding glutamine cycling as a transient dynamic phenomenon, or a prominent role of GABA reuptake. Redox balance is proposed as an explanation for elevated oxidative phosphorylation and adenosine triphosphate hydrolysis in astrocytes, decoupled from energy requirements. [ABSTRACT FROM AUTHOR]

Abstract: In the study presented here, a mathematical approach for the deposition and clearance of rigid and chemically stable fibers in the human respiratory tract (HRT) is described in detail. For the simulation of fiber transport and deposition in lung airways an advanced concept of the aerodynamic diameter is applied to a stochastic lung model with individual particle trajectories computed according to a random walk algorithm. Interception of fibrous material at airway bifurcations is considered by implementation of correction factors obtained from previously published numerical approaches to fiber deposition in short bronchial sequences. Fiber clearance is simulated on the basis of a multicompartment model, within which separate clearance scenarios are assumed for the alveolar, bronchiolar, and bronchial lung region and evacuation of fibrous material commonly takes place via the airway and extrathoracic path to the gastrointestinal tract (GIT) or via the transepithelial path to the lymph nodes and blood vessels. Deposition of fibrous particles in the HRT is controlled by the fiber aspect ratio β in as much as particles with diameters <0.1μm deposit less effectively with increasing β, while larger particles exhibit a positive correlation between their deposition efficiencies and β. A change from sitting to light-work breathing conditions causes only insignificant modifications of total fiber deposition in the HRT, whereas alveolar and, above all, tubular deposition of fibrous particles with a diameter ≥0.1μm are affected remarkably. For these particles enhancement of the inhalative flow rate results in an increase of the extrathoracic and bronchial deposition fractions. Concerning the clearance of fibers from the HRT, 24-h retention is noticeably influenced by β and, not less important, by the preferential deposition sites of the simulated particles. The significance of β with respect to particle size may be regarded as similar to that determined for the deposition scenarios, while breathing conditions do not have a valuable effect on clearance. [Copyright &y& Elsevier]

The steady state and terminal (area) volumes of distribution are important pharmacokinetic parameters defined as the ratio of the total quantity of drug in the body, Ab(t), to drug plasma concentration Cp(t) at steady state and the terminal phase of drug elimination, respectively. The general equations for the approach of Cp(t), Ab(t) and the distribution volume Ab(t)/Cp(t) to the steady state values (for a continuous constant rate drug infusion) are derived. It is shown that the time course of Ab(t) near the asymptotic steady state value depends on both the terminal and steady state volumes of distribution, and an accurate equation to determine the time required to reach the steady state is obtained. For a general linear pharmacokinetic system (i.e., with possible drug elimination at any state from any compartment and drug exchange between compartments) it is proven that Vβ ≥ Vss. A physiologically determined feature, which is the drug input into plasma for reaching the steady state or terminal phase, underlies the proof. If the steady state is reached by a continuous input of drug into some compartment other than plasma, and the terminal volume of distribution is considered after dosing of a drug in the same compartment, then both cases Vss ≶ Vβ are possible. It is shown that the general exponential series for Cp(t) after intravenous bolus dose may have negative pre-exponents, unlike a common assumption that all pre-exponents should be positive. Its is figured out that the commonly used equations for the estimation of Vss and Vβ (Vss = D · AUMC/AUC2 and Vβ = D/(AUC · β) may yield Vss > Vβ for a linear pharmacokinetic system, contrary to the usual statement (Vss < Vβ) and its seemingly simple proof, which has a flaw. It is shown that the time required to reach the steady state concentration of drug in plasma could be much shorter than a commonly used estimation of 5t1/2, where t1/2 is the terminal half-life obtained from the intravenous bolus drug plasma concentration time course. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:1638–1652, 2007 [ABSTRACT FROM AUTHOR]

A deconvolution approach is presented to solve fiber crossing in diffusion magnetic resonance imaging. In order to provide a direct physical interpretation of the signal generation process, we started from the classical multicompartment model and rewrote this in terms of a convolution process, identifying a significant scalar parameter α to characterize the physical system response. Deconvolution is performed by a modified version of the Richardson-Lucy algorithm. Simulations show the ability of this method to correctly separate fiber crossing, even in the presence of noisy data, with lower signal-to-noise ratio, and imprecision in the impulse response function imposed during deconvolution. The in vivo data confirms the efficacy of this method to resolve fiber crossing in real complex brain structures. These results suggest the usefulness of our approach in fiber tracking or connectivity studies. [ABSTRACT FROM AUTHOR]

The estimation of a large number of parameters in a complex dynamic multicompartment model in the presence of insufficient data is a difficult and challenging problem. Such problems arise in many applications, e.g., in biology, physiology, and environmental sciences. The model consists of a large system of coupled nonlinear ordinary differential equations, the data consisting of the values of few components at given observation times. The estimation problems are usually ill-posed and severely underdetermined, while the quality of the scarce data is far from optimal. Therefore, a successful solution necessarily requires additional information about the parameters. A natural framework to introduce a priori information into the model is the Bayesian paradigm. In this article we develop a Bayesian methodology that is able to utilize various types of prior constraints such as approximate algebraic constraints for the parameters or inequality constraints for the solutions and integrate them into a parametric prior distribution. The subsequent parameter estimation is based on a combination of optimization methods and statistical sampling techniques. We apply the methodology to a skeletal muscle metabolism model, in which we are able to simultaneously estimate more than 100 parameters from one fifth as many measured data points. [ABSTRACT FROM AUTHOR]

Background: The volume of distribution at steady state for ethanol (Vss) is thought to be identical to the total body water (TBW). We compared a two-compartment pharmacokinetic model with parallel Michaelis-Menten and first-order renal elimination with the classical one-compartment zero-order elimination model. Ethanol concentration-time profiles were established for breath, venous blood, and urine. The values of Vss obtained for ethanol were compared with TBW determined by deuterium oxide dilution. Methods: Sixteen healthy volunteers each received a 30-min intravenous infusion of ethanol on two occasions. Ethanol was measured in breath by a quantitative infrared analyzer and in blood and urine by headspace gas chromatography. Deuterium oxide was given as an intravenous injection and measured in serum by isotope-ratio mass spectrometry. Components of variation were calculated by ANOVA to determine the precision of the estimates of Vss and TBW. Results: Mean TBW, determined by deuterium oxide dilution, was 44.1 ± 3.9 liters (±SD) for men, corresponding to 0.61 liters/kg, and 37.4 ± 3.2 liters for women, or 0.54 liters/kg. Estimates of Vss from blood-ethanol pharmacokinetics were 87.6% of TBW according to isotope dilution and 84.4% for breath analysis with the two-compartment model. This compares with 95.1% and 95.4% for blood and breath alcohol, respectively, when the classical zero-order kinetic analysis is used. The precision of the estimates of Vss and TBW was between ±1.56 and ±2.19 liters (95% confidence interval). Conclusions: Ethanol does not distribute uniformly into the TBW. The precision of measuring Vss by ethanol dilution was comparable to estimates of TBW by isotope dilution. Results of noninvasive breath ethanol analysis compared well with use of venous blood for estimating Vss. The sophisticated two-compartment model was much superior to the classical one-compartment model in explaining the total concentration-time course of intravenously given ethanol. [ABSTRACT FROM AUTHOR]

Inverse solution techniques based on electroencephalograph (EEG) measurements have become a powerful means of gaining knowledge about the functioning of the brain. A model of the head and a potential computation method are necessary to describe the EEG problem mathematically. The generation of realistically shaped three-compartment models of the head is discussed. The isolated problem approach for the boundary element method is applied to develop a fast and accurate numerical solution of the EEG forward problem. Accuracy studies with this approach show that dipole positions can be reconstructed within a distance of 3 mm from the original positions. Inverse simulations indicate that the incorporation of the individual head shape may significantly influence the reconstructed dipole position but not its magnitude and orientation, in comparison with the commonly used three-sphere model. However, the presence of noise in the simulated potential data affects the solutions based on realistically shaped models more than those of the simple three-sphere model. The increased sensitivity of the former models to noise in the data remains a serious drawback for their practical application to EEG source localisations. [ABSTRACT FROM AUTHOR]

Objective. Invasive simultaneous stimulation and recording from intracranial electrodes and microwire arrays were used to investigate direct cortical responses to single pulses of electrical stimulation in humans. Approach. Microwire contacts measured surface potentials in cortical microdomains at a distance of 2-6 mm from the intracranial electrode. Direct cortical responses to stimulation (<20 ms) consisted of a larger surface negative potentials. Main results . The latencies of these responses were directly or inversely correlated with distances between the intracranial electrode and microwire contacts. We hypothesize that surface negative potentials reflected local synchronous depolarization of apical dendrites of pyramidal neurons in cortical microdomains in the superficial cortical layer and resulted from the activation of gray matter axons that delivered excitatory inputs to apical dendrites after cortical stimulation. We further hypothesized that the positive or inverse distance-latency correlations of the recorded negative responses were measured depending on whether activation of neurons originated at one (crown) or multiple (crown, lip, bank) sites throughout the gyrus simultaneously. The inverse distance-latency correlations then reflected the spatiotemporal superposition of different nearby sources of neuronal recruitment in the gyrus. To prove this hypothesis, we built an anatomically informed and biophysically realistic cortical network model and simulated early responses of cortical neurons to electrical stimulation in this cortical network model. The model simulations yielded negative potentials in simulated microdomains in the cortical model consistent with those recorded from humans. The model predicted sensitivity of cortical responses to the alignment of the stimulating electrode and microwire array with respect to the cortical gyrus and confirmed that gyral geometry has a major impact on direct neuronal recruitment, the timing, and the time course of neuronal activation in cortical microdomains. Significance. In this work, we demonstrated how the high-resolution forward network models can be used for better understanding and detailed prediction of cortical stimulation effects. Accurate predictive modeling tools are needed for the progress of brain stimulation therapies., (© 2021 IOP Publishing Ltd.)

Background: There is a need for new approaches to increase the knowledge of the membrane excitability of small nerve fibers both in healthy subjects, as well as during pathological conditions. Our research group has previously developed the perception threshold tracking technique to indirectly assess the membrane properties of peripheral small nerve fibers. In the current study, a new approach for studying membrane excitability by cooling small fibers, simultaneously with applying a slowly increasing electrical stimulation current, is evaluated. The first objective was to examine whether altered excitability during cooling could be detected by the perception threshold tracking technique. The second objective was to computationally model the underlying ionic current that could be responsible for cold induced alteration of small fiber excitability. The third objective was to evaluate whether computational modelling of cooling and electrical simulation can be used to generate hypotheses of ionic current changes in small fiber neuropathy.Results: The excitability of the small fibers was assessed by the perception threshold tracking technique for the two temperature conditions, 20 °C and 32 °C. A detailed multi-compartment model was developed, including the ionic currents: NaTTXs, NaTTXr, NaP, KDr, KM, KLeak, KA, and Na/K-ATPase. The perception thresholds for the two long duration pulses (50 and 100 ms) were reduced when the skin temperature was lowered from 32 to 20 °C (p < 0.001). However, no significant effects were observed for the shorter durations (1 ms, p = 0.116; 5 ms p = 0.079, rmANOVA, Sidak). The computational model predicted that the reduction in the perception thresholds related to long duration pulses may originate from a reduction of the KLeak channel and the Na/K-ATPase. For short durations, the effect cancels out due to a reduction of the transient TTX resistant sodium current (Nav1.8). Additionally, the result from the computational model indicated that cooling simultaneously with electrical stimulation, may increase the knowledge regarding pathological alterations of ionic currents.Conclusion: Cooling may alter the ionic current during electrical stimulation and thereby provide additional information regarding membrane excitability of small fibers in healthy subjects and potentially also during pathological conditions. [ABSTRACT FROM AUTHOR]

Objective: Computational modeling studies were performed to identify presynaptic elements of cortical neurons that are activated by subdural electrical stimulation., Materials and Methods: The computer model consists of layers of multicompartmental neurons arranged in 3D space in an anatomically realistic fashion inside a 4.8 × 4.8 × 3.4 mm volume of gray matter modeled as a homogenous and isotropic medium. The model was subjected to an electric field generated by a circular disk electrode., Results: The initiation of presynaptic action potentials (PAPs) in neurons takes place predominantly in the axon initial segment (AIS) or ectopically in axonal branch terminals. PAPs that were initiated in only one axonal terminal were typically followed by a second PAP (spike duplet) resulting from the activation of the AIS by the antidromically propagating initial PAP. There were significant time delays (up to 0.5 ms) in the propagation of these ectopically initiated PAPs along the axons to nonactivated axonal branches and, associated with these delays, latencies in the occurrence of spike duplets in different axonal terminals. The effect of the dendritic arbor 3D structure on the AIS activation threshold was contingent on whether the net axonal and somato-dendritic current flows made an antagonistic or synergetic contribution., Conclusions: This study examines the effects of subdural electrical stimulation on a high-density network consisting of several populations of multicompartment cell types. The effect of dendritic arbor structure on the axonal activation threshold is prominent in the case of multipolar neurons with large-diameter symmetric dendrites (basal/apical) that are oriented parallel to the electric field lines. The timing of presynaptic terminal activation after stimulation is not determined solely by the axonal delay (orthodromic propagation) but depends on the details of the applied stimulation field and axonal branching structure, which may be important factors in characterizing the effects of electrical stimulation in neuromodulation systems., (© 2015 International Neuromodulation Society.)