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At least 19 recordsLinked to original sources
PubMed1991

Model of kinetic behavior of deoxyglucose in heterogeneous tissues in brain: a reinterpretation of the significance of parameters fitted to homogeneous tissue models.

Effects of tissue heterogeneity on regional CMRglc (rCMRglc) calculated by use of the deoxyglucose (DG) method at 45 min following the pulse of DG were evaluated in simulation studies. A theoretical model was developed to describe the kinetics of DG uptake and metabolism in heterogeneous brain tissues. Rate constants were fitted to simulation data for mixed tissue and rCMRglc computed on the basis of this tissue heterogeneity model. The results were compared with those obtained by use of the original model of the DG method for homogeneous tissue, both without (3K model) and with (4K model) a term to describe an apparent loss of deoxyglucose-6-phosphate (DG-6-P). As a direct consequence of tissue heterogeneity, the effective rate constant for phosphorylation of DG, k3*, declined with time. To compensate for the time-changing k3*, estimates of the dephosphorylation rate constant, k4*, were artifactually high when the 4K model was used, even though no dephosphorylation of DG-6-P actually occurred. The present study demonstrates that the finding of a significant k4*, at least within 45 min following a pulse of DG, may not represent dephosphorylation at all, but rather the consequence of measuring radioactivity in a heterogeneous tissue and applying a model designed for a homogeneous tissue. Furthermore, the high estimates of k4* resulted in significant overestimation of rCMRglc. When rCMRglc was computed with the conventional single-scan or autoradiographic method at 45 min after a pulse of DG, the 3K and tissue heterogeneity models yielded values that were within 5% of the true weighted average value for the heterogeneous tissue as a whole. We conclude that the effects of tissue heterogeneity alone can give the appearance of product loss, even when none occurs, and that the use of the 4K model with the assumption of product loss in the 45-min experimental period recommended for the DG method may lead to overestimation of the rates of glucose utilization.

Brain↗
PubMed2001

A computationally efficient algorithm for determining regional cerebral blood flow in heterogeneous tissues by positron emission tomography.

Inclusion of brain tissues with different rates of blood flow and metabolism within a voxel or region of interest is an unavoidable problem with positron emission tomography due to its limited spatial resolution. Because regional cerebral blood flow (rCBF) is higher in gray matter than in white matter, the partial volume effect leads to underestimation of rCBF in gray matter when rCBF in the region as a whole is determined. Furthermore, weighted-average rCBF itself is underestimated if the kinetic model used in the analysis fails to account for the tissue heterogeneity. We have derived a computationally efficient method for estimating both gray matter and weighted-average rCBF in heterogeneous tissues and validated the method in simulation studies. The method is based on a model that represents a heterogeneous tissue as a weighted mixture of two homogeneous tissues. A linear least squares algorithm is used to estimate the model parameters.

Algorithms↗
PubMed1993

Measurement of regional cerebral glucose utilization with fluorine-18-FDG and PET in heterogeneous tissues: theoretical considerations and practical procedure.

Functional tissue heterogeneity, i.e., inclusion of tissues with different rates of blood flow and metabolism within a single region of interest, is an unavoidable problem with PET. Errors in determination of regional cerebral glucose utilization (rCMRglc) with [18F]FDG have resulted from the currently used simplifying assumption that all regions examined are homogeneous. We have established an optimal, yet practical procedure to minimize errors due to tissue heterogeneity in determination of rCMRglc. Effects of applying the three-rate constant kinetic model designed for homogeneous tissues with both dynamic and single-scan procedures and the Patlak plot were evaluated in normal subjects in experimental periods up to 120 min following tracer injection. The procedure with a single scan carried out any time within the interval between 60 and 120 min following tracer injection, combined with population average rate constants determined over a 120-min period, was found to be optimal for quantitative rCMRglc studies.

Adult↗
PubMed2003

Non-invasive assessment of distribution volume ratios and binding potential: tissue heterogeneity and interindividually averaged time-activity curves.

Due to the stochastic nature of radioactive decay, any measurement of radioactivity concentration requires spatial averaging. In pharmacokinetic analysis of time-activity curves (TAC), such averaging over heterogeneous tissues may introduce a systematic error (heterogeneity error) but may also improve the accuracy and precision of parameter estimation. In addition to spatial averaging (inevitable due to limited scanner resolution and intended in ROI analysis), interindividual averaging may theoretically be beneficial, too. The aim of this study was to investigate the effect of such averaging on the binding potential ( BP) calculated with Logan's non-invasive graphical analysis and the "simplified reference tissue method" (SRTM) proposed by Lammertsma and Hume, on the basis of simulated and measured positron emission tomography data [[(11)C] d- threo-methylphenidate (dMP) and [(11)C]raclopride (RAC) PET]. dMP was not quantified with SRTM since the low k(2) (washout rate constant from the first tissue compartment) introduced a high noise sensitivity. Even for considerably different shapes of TAC (dMP PET in parkinsonian patients and healthy controls, [(11)C]raclopride in patients with and without haloperidol medication) and a high variance in the rate constants (e.g. simulated standard deviation of K(1)=25%), the BP obtained from average TAC was close to the mean BP (error <5%). However, unfavourably distributed parameters, especially a correlated large variance in two or more parameters, may lead to larger errors. In Monte Carlo simulations, interindividual averaging before quantification reduced the variance from the SRTM (beyond a critical signal to noise ratio) and the bias in Logan's method. Interindividual averaging may further increase accuracy when there is an error term in the reference tissue assumption E= DV(2)- DV' ( DV(2) = distribution volume of the first tissue compartment, DV' = distribution volume of the reference tissue). This can be explained by the fact that the distribution volume ratio ( DVR= DV/DV') obtained from averaged TAC is an approximation for Sigma DV/Sigma DV' rather than for Sigma DVR/ n. We conclude that Logan's non-invasive method and SRTM are suitable for heterogeneous tissues and that discussion of group differences in PET studies generally should include qualitative and quantitative assessment of interindividually averaged TAC.

Computer Simulation↗
PubMedDate not supplied

Dosimetric evaluation in heterogeneous tissue of anterior electron beam irradiation for treatment of retinoblastoma.

A dosimetric study of anterior electron beam irradiation for treatment of retinoblastoma was performed to evaluate the influence of tissue heterogeneities on the dose distribution within the eye and the accuracy of the dose calculated by a pencil beam algorithm. Film measurements were made in a variety of polystyrene phantoms and in a removable polystyrene eye incorporated into a tissue substitute phantom constructed from a human skull. Measurements in polystyrene phantoms were used to demonstrate the algorithm's ability to predict the effect of a lens block placed in the beam, as well as the eye's irregular surface shape. The eye phantom was used to measure dose distributions within the eye in both the sagittal and transverse planes in order to test the algorithm's ability to predict the dose distribution when bony heterogeneities are present. Results show (1) that previous treatment planning conclusions based on flat, uniform phantoms for central-axis depth dose are adequate; (2) that a three-dimensional heterogeneity correction is required for accurate dose calculations; and (3) that if only a two-dimensional heterogeneity correction is used in calculating the dose, it is more accurate for the sagittal than the transverse plane.

Electrons↗
PubMed2004

Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue.

The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the I(Ks) channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of beta-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with beta-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between beta-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.

Action Potentials↗
PubMed2006

EEG human head modelling based on heterogeneous tissue conductivity.

This paper studies the effect of heterogeneous tissue conductivity in a human head model for the EEG forward problem. Firstly, the tissue heterogeneity in conductivity was characterised from measured data in the literature. Then a method was developed to include this feature in modelling. Finally, the effect of tissue heterogeneity on EEG signals was studied. Based on these studies the paper concludes that the inclusion of tissue heterogeneity is significant in accurate head modelling for the EEG problem.

Action Potentials↗
PubMed2006

Deconfounding microarray analysis - independent measurements of cell type proportions used in a regression model to resolve tissue heterogeneity bias.

OBJECTIVES: Microarray analysis requires standardized specimens and evaluation procedures to achieve acceptable results. A major limitation of this method is caused by heterogeneity in the cellular composition of tissue specimens, which frequently confounds data analysis. We introduce a linear model to deconfound gene expression data from tissue heterogeneity for genes exclusively expressed by a single cell type. METHODS: Gene expression data are deconfounded from tissue heterogeneity effects by analyzing them using an appropriate linear regression model. In our illustrating data set tissue heterogeneity is being measured using flow cytometry. Gene expression data are determined in parallel by real time quantitative polymerase chain reaction (qPCR) and microarray analyses. Verification of deconfounding is enabled using protein quantification for the respective marker genes. RESULTS: For our illustrating dataset, quantification of cell type proportions for peripheral blood mononuclear cells (PBMC) from tuberculosis patients and controls revealed differences in B cell and monocyte proportions between both study groups, and thus heterogeneity for the tissue under investigation. Gene expression analyses reflected these differences in celltype distribution. Fitting an appropriate linear model allowed us to deconfound measured transcriptome levels from tissue heterogeneity effects. In the case of monocytes, additional differential expression on the single cell level could be proposed. Protein quantification verified these deconfounded results. CONCLUSIONS: Deconfounding of transcriptome analyses for cellular heterogeneity greatly improves interpretability, and hence the validity of transcriptome profiling results.

Cell Physiological Phenomena↗
PubMed1995

Effect of tissue heterogeneity on quantification in positron emission tomography.

As a result of the limited spatial resolution of positron emission tomographic scanners, the measurements of physiological parameters are compromised by tissue heterogeneity. The effect of tissue heterogeneity on a number of parameters was studied by simulation and an analytical method. Five common tracer models were assessed. The input and tissue response functions were assumed to be free from noise and systematic errors. The kinetic model was assumed to be perfect. Two components with different kinetics were mixed in different proportions and contrast with respect to the model parameters. Different experimental protocols were investigated. Of three methods investigated for the measurement of cerebral blood flow (CBF) (steady state, dynamic, integral), the second one was least sensitive to errors caused by tissue heterogeneity and the main effect was an underestimation of the distribution volume. With the steady state method, errors in oxygen extraction fraction caused by tissue heterogeneity were always found to be less than the corresponding errors in CBF. For myocardial blood flow the steady state method was found to perform better than the bolus method. The net accumulation of substrate (i.e. rCMRglc in the case of glucose analogs) was found to be comparatively insensitive to tissue heterogeneity. Individual rate constants such as k2 and k3 for efflux and metabolism of the substrate in the pool of unmetabolized substrate in the tissue, respectively, were found to be more sensitive. In studies of radioligand binding, using only tracer doses, the effect of tissue heterogeneity on the parameter kon.Bmax could be considerable. In studies of radioligand binding using a protocol with two experiments, one with high and one with low specific activity, Bmax was found to be insensitive while Kd was very sensitive to tissue heterogeneity.

Body Water↗
PubMed1985

Influence of tissue heterogeneity on the determination of steroid receptors in breast cancer.

Biochemical determination of hormone receptors in carcinomas is influenced by the potential heterogeneity of the tissue samples. In order to check this, samples of 16 breast cancers were divided into 6 segments. These segments were alternately examined for their ratio of tumor tissue to connective tissue ("percentage of carcinoma") or for the content of estrogen and progesterone receptors. Only 3 of the tumors were homogeneous, and 9 of the heterogeneous tissues had hormone receptors. The segment with the maximum "percentage of carcinoma" was adjacent to that with the peak value of hormone receptors in all but 1 tissue. The same applied to the minima. The maximum and minimum values of estrogen and progesterone receptors were located within the same segment in all but one tissue sample. The results demonstrated that biochemical assay of hormone receptors is reliable. A reduction of the sample volume does not enhance the precision of the receptor assay, since it increases the possibility of a false negative result.

Adenocarcinoma, Mucinous↗
PubMed1992

Errors introduced by tissue heterogeneity in estimation of local cerebral glucose utilization with current kinetic models of the [18F]fluorodeoxyglucose method.

The effects of tissue heterogeneity on the estimation of regional cerebral glucose utilization (rCMRglc) in normal humans with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) were compared with respect to the various kinetic models of the [18F]FDG method. The kinetic models were conventional homogeneous tissue models of the [18F]FDG method, with (4K Model) and without (3K Model) a rate constant to account for an apparent loss of [18F]2-fluoro-2-deoxy-D-glucose-6-phosphate ([18F]FDG-6-P), and a tissue heterogeneity model (TH Model). When either of the kinetic models designed for homogeneous tissues was applied to heterogeneous tissues, estimates of the rate constant for efflux of [18F]FDG from the tissue (k2*) and of the rate constant for phosphorylation of [18F]FDG (k3*) decreased as the duration of the experimental period was increased. When the 4K Model was used, estimates of the rate constant for the apparent dephosphorylation of [18F]FDG-6-P (k4*) were significantly greater than zero and fell with increasing duration of the experimental period. Although the TH Model included no term to describe an apparent dephosphorylation of [18F]FDG-6-P, the fit of the TH Model to the time course of total tissue radioactivity was at least as good as and often better than the fit of the 4K Model in the 120-min period following the pulse of [18F]FDG. Hence, the high estimates of k4* found in PET studies of less than or equal to 120 min can be explained as the consequence of measuring radioactivity in a heterogeneous tissue and applying a model designed for a homogeneous tissue; there remains no evidence of significant dephosphorylation of [18F]FDG-6-P in this time period. Furthermore, use of the 4K Model led to an overestimation of rCMRglc; whole-brain glucose utilization calculated with the 4K Model was greater than 20% higher than values usually obtained in normal humans by the model-independent Kety-Schmidt technique. rCMRglc was accurately estimated by the TH Model and, in experimental periods sufficiently long to minimize the effects of tissue heterogeneity, also by the original 3K Model of the deoxyglucose method.

Adult↗
PubMed1992

Low oxygen extraction fraction in tumours measured with the oxygen-15 steady state technique: effect of tissue heterogeneity.

Several reports have described decreased oxygen extraction fractions in tumours relative to those in normal tissues as measured with the oxygen-15 steady state technique and positron emission tomography. The present simulation study was carried out to assess the influence of tissue heterogeneity on these measured values. It was found that, within the range analyzed, tissue heterogeneity always resulted in underestimations of mean values of oxygen extraction fraction. It must, therefore, be concluded that the oxygen-15 steady state technique is not an accurate method for the assessment of the oxygen status of tumours. This finding should also apply to other pathological conditions, where a significant degree of tissue heterogeneity can not be excluded. More generally, this study demonstrates the need for detailed analyses of sensitivities of tracer kinetic procedures to tissue heterogeneity.

Brain Neoplasms↗
PubMed2004

Tissue heterogeneity in the mouse lung: effects of elastase treatment.

We developed a network model in an attempt to characterize heterogeneity of tissue elasticity of the lung. The model includes a parallel set of pathways, each consisting of an airway resistance, an airway inertance, and a tissue element connected in series. The airway resistance, airway inertance, and the hysteresivity of the tissue elements were the same in each pathway, whereas the tissue elastance (H) followed a hyperbolic distribution between a minimum and maximum. To test the model, we measured the input impedance of the respiratory system of ventilated normal and emphysematous C57BL/6 mice in closed chest condition at four levels of positive end-expiratory pressures. Mild emphysema was developed by nebulized porcine pancreatic elastase (PPE) (30 IU/day x 6 days). Respiratory mechanics were studied 3 wk following the initial treatment. The model significantly improved the fitting error compared with a single-compartment model. The PPE treatment was associated with an increase in mean alveolar diameter and a decrease in minimum, maximum, and mean H. The coefficient of variation of H was significantly larger in emphysema (40%) than that in control (32%). These results indicate that PPE treatment resulted in increased time-constant inequalities associated with a wider distribution of H. The heterogeneity of alveolar size (diameters and area) was also larger in emphysema, suggesting that the model-based tissue elastance heterogeneity may reflect the underlying heterogeneity of the alveolar structure.

Airway Resistance↗
PubMed2005

Effects of tissue heterogeneity on cerebral vascular response to acetazolamide stress measured by an I-123-IMP autoradiographic method with single-photon emission computed tomography.

OBJECTIVES: Single-photon emission computed tomography (SPECT) with iodine-123 (123I)-labeled N-isopropyl-p-iodoamphetamine (IMP) is widely used in measuring the cerebral blood flow (CBF) response to acetazolamide stress for assessment of cerebral vascular reserve. To quantitate CBF by means of SPECT with IMP, an autoradiographic (ARG) method has been developed and is widely used. Because the relation between the brain counts on the SPECT scan and CBF is not linear in the ARG method, a mixture of gray and white matter in a pixel causes errors in the calculation of CBF. In the present study, errors in the calculation of CBF and vascular response to acetazolamide stress by the ARG method due to tissue heterogeneity were estimated by simulation study. Correction for effects of tissue heterogeneity in SPECT data was also attempted. METHODS: Images of gray and white matter fraction were obtained by voxel-based morphometry analysis of magnetic resonance (MR) imaging data set. Ideal CBF images, which were generated from gray and white matter fraction images with assumed blood flow values for gray and white matter, were compared to CBF images generated by the ARG method. Correction for effects of tissue heterogeneity in SPECT data was performed with gray and white matter fraction data obtained from MR images. RESULTS: Systematic underestimation of CBF due to tissue heterogeneity was observed in all brain regions. In the neocortical regions, underestimation by -21% to -16%, -26% to -20%, -31% to -24%, and -35% to -27% was observed for gray and white matter blood flow of 80 and 20, 100 and 25, 120 and 30, and 140 and 35 ml/100 ml/min, respectively. Vascular response was also systematically underestimated in most brain regions. Vascular responses in the neocortical regions ranged from 17% to 20%, from 31% to 37%, and from 42% to 52% when ideal vascular responses were 25%, 50%, and 75%, respectively. After correction for the effects of tissue heterogeneity, values of vascular response to acetazolamide stress ranged from 64% to 116% in the neocortical regions, whereas values obtained by the ARG method ranged from 48% to 52%. CONCLUSION: Underestimation of the vascular response to acetazolamide stress due to tissue heterogeneity should be considered in the estimation of cerebral vascular reserve.

Acetazolamide↗
PubMed1987

The influence of tissue heterogeneity on results of fitting nonlinear model equations to regional tracer uptake curves: with an application to compartmental models used in positron emission tomography.

An analytical method based on Taylor expansions was developed to analyze errors caused by tissue heterogeneity in dynamic positron emission tomography (PET) measurements. Some general rules concerning the effect of parameter variances and covariances were derived. The method was further applied to various compartmental models currently used for measurement of blood flow, capillary permeability, glucose metabolism, and tracer binding. Blood flow and capillary permeability are shown to be generally underestimated in heterogeneous tissue, the underestimation being more severe for slowly decaying, constant or increasing input functions rather than for bolus input, and increasing with measurement time. Typical errors caused by the heterogeneity due to insufficient separation between gray and white matter by a PET scanner with full width at half-maximum (FWHM) = 5 to 10 mm resolution range between -0.9 and -6% in dynamic CBF measurements with intravenous (i.v.) bolus injection of 15O-water or inhalation of 18F-fluoromethane and total measurement times of 6 or 10 min, respectively. Binding or metabolic rates determined with tracers that are essentially trapped in tissue (e.g., FDG for measurement of cerebral glucose metabolism) are only slightly overestimated (0.5-3.0%) at typical measurement times and are essentially independent of the shape of the input function. The error increase considerably if tracer accumulation is very slow, however, or if short measurement times [less than 5/(k2 + k3)] are used. Some rate constants are also subject to larger errors.

Blood-Brain Barrier↗
PubMed2026

Accurately Deciphering Tissue Heterogeneity From Spatial Multi-Modal and Multi-Omics With STransformer.

Advances in spatially resolved technologies enable the simultaneous acquisition of diverse data modalities within a tissue slice while preserving critical spatial context, which presents unprecedented opportunities to decipher intricate tissue heterogeneity. However, existing computational approaches lack the intrinsic flexibility to universally process both spatial multi-modal and multi-omics data. Here, we introduce STransformer, a unified deep learning framework designed to seamlessly accommodate a comprehensive landscape of spatial data. By simultaneously capturing short-range cellular interactions and tissue-wide semantic patterns, it extracts robust representations to accurately dissect complex tissue heterogeneity. Systematic evaluations across diverse species, tissue types, and data modalities highlight its profound versatility. For spatial multi-modal data, STransformer delineates intricate anatomical structures in the human cortex, uncovers pathological mechanisms in Alzheimer's disease, and characterizes dynamic spatiotemporal developmental trajectories during chicken cardiogenesis. Scaling to spatial multi-omics data, STransformer synergizes spatial transcriptomic and proteomic profiles to decipher intricate immune microenvironments within the human tonsil, and jointly analyzes spatial epigenomic and transcriptomic data to infer regulatory mechanisms in the mouse embryonic brain. Consequently, STransformer serves as a highly versatile and robust analytical framework for advancing our understanding of tissue heterogeneity and disease&#xa0;pathogenesis.

Multiomics↗
PubMed2000

Statistically driven identification of focal metabolic abnormalities in temporal lobe epilepsy with corrections for tissue heterogeneity using 1H spectroscopic imaging.

1H spectroscopic imaging of N-acetyl-aspartate, creatine, and choline has proven to be a sensitive indicator for the lateralization of seizure foci in temporal lobe epilepsy. Previous studies have used right-left comparisons to identify the epileptogenic tissue assuming that alterations due to the disease process outweigh the effects of tissue heterogeneity. To evaluate the effectiveness of tissue heterogeneity corrected analyses, we evaluated three criteria for lateralization of the seizure focus: 1) a statistically driven method adjusted for tissue composition, 2) a single valued threshold, and 3) a single global index of the hippocampus. The statistically driven analysis lateralized all eight patients correctly, whereas the single threshold method incorrectly lateralized one case and the global index failed to identify a significant difference in two cases. These findings indicate that increased accuracy and sensitivity can be obtained by correcting for tissue heterogeneity when analyzing spectroscopy studies of temporal lobe epilepsy.

Adult↗