Modeling the hematocrit distribution in microcirculatory networks: A quantitative evaluation of a phase separation model.

OBJECTIVE: Theoretical models are essential tools for studying microcirculatory function. Recently, the validity of a well-established phase separation model was questioned and it was claimed that it produces problematically low hematocrit predictions and lack of red cells in small diameter vessels. We conducted a quantitative evaluation of this phase separation model to establish common ground for future research. METHODS: Model predictions were validated against a comprehensive database with measurements from 4 mesenteric networks. A Bayesian data analysis framework was used to integrate measurements and network model simulations into a combined analysis and to model uncertainties related to network boundary conditions as well as phase separation model parameters. The model evaluation was conducted within a cross-validation scheme. RESULTS: Unlike the recently reported results, our analysis demonstrated good correspondence in global characteristics between measurements and predictions. In particular, predicted hematocrits for vessels with small diameters were consistent with measurements. Incorporating phase separation model parameter uncertainties further reduced the hematocrit validation error by 17% and led to the absence of red-cell-free segments. Corresponding model parameters are presented as alternatives to standard parameters. CONCLUSIONS: Consistent with earlier studies, our quantitative model evaluation supports the continued use of the established phase separation model.

Model-based inference from microvascular measurements: Combining experimental measurements and model predictions using a Bayesian probabilistic approach.

OBJECTIVE: In vivo imaging of the microcirculation and network-oriented modeling have emerged as powerful means of studying microvascular function and understanding its physiological significance. Network-oriented modeling may provide the means of summarizing vast amounts of data produced by high-throughput imaging techniques in terms of key, physiological indices. To estimate such indices with sufficient certainty, however, network-oriented analysis must be robust to the inevitable presence of uncertainty due to measurement errors as well as model errors. METHODS: We propose the Bayesian probabilistic data analysis framework as a means of integrating experimental measurements and network model simulations into a combined and statistically coherent analysis. The framework naturally handles noisy measurements and provides posterior distributions of model parameters as well as physiological indices associated with uncertainty. RESULTS: We applied the analysis framework to experimental data from three rat mesentery networks and one mouse brain cortex network. We inferred distributions for more than 500 unknown pressure and hematocrit boundary conditions. Model predictions were consistent with previous analyses, and remained robust when measurements were omitted from model calibration. CONCLUSION: Our Bayesian probabilistic approach may be suitable for optimizing data acquisition and for analyzing and reporting large data sets acquired as part of microvascular imaging studies.

PHYCAA: data-driven measurement and removal of physiological noise in BOLD fMRI.

The effects of physiological noise may significantly limit the reproducibility and accuracy of BOLD fMRI. However, physiological noise evidences a complex, undersampled temporal structure and is often non-orthogonal relative to the neuronally-linked BOLD response, which presents a significant challenge for identifying and removing such artifact. This paper presents a multivariate, data-driven method for the characterization and removal of physiological noise in fMRI data, termed PHYCAA (PHYsiological correction using Canonical Autocorrelation Analysis). The method identifies high frequency, autocorrelated physiological noise sources with reproducible spatial structure, using an adaptation of Canonical Correlation Analysis performed in a split-half resampling framework. The technique is able to identify physiological effects with vascular-linked spatial structure, and an intrinsic dimensionality that is task- and subject-dependent. We also demonstrate that increasing dimensionality of such physiological noise is correlated with increasing variability in externally-measured respiratory and cardiac processes. Using PHYCAA as a denoising technique significantly improves simulated signal detection with physiological noise, and real data-driven model prediction and reproducibility, for both block and event-related task designs. This is demonstrated compared to no physiological noise correction, and to the widely used RETROICOR (Glover et al., 2000) physiological denoising algorithm, which uses externally measured cardiac and respiration signals.

APOE gene-dependent BOLD responses to a breath-hold across the adult lifespan.

Age and apolipoprotein E (APOE) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the APOE e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxide (NO) source. The study was designed as a randomized, double-blinded, placebo-controlled crossover study, and the study cohort comprised 41 APOE e4 carriers (e3/e4 or e4/e4 genotype) and 40 non-carriers (e3/e3 genotype) aged 30-70 years at enrollment. The participants underwent two scanning sessions, each preceded by ingestion of sodium nitrate or sodium chloride (control). During functional magnetic resonance imaging (fMRI) sessions, participants performed two concurrent tasks; a breath-hold task to probe cerebrovascular reactivity and a visual stimulation task to evoke functional hyperemia, respectively. We found that the blood oxygenation level dependent (BOLD) hemodynamic response to breath-hold was altered in APOE e4 carriers relative to non-carriers. Mid-aged (50-60 years of age) e4 carriers exhibited a significantly increased peak time relative to mid-aged e3 carriers, and peak time for younger (30-40 years of age) e4 carriers was significantly shorter than that of mid-aged e4 carriers. The response width was significantly increased for e4 carriers. The response peak magnitude significantly decreased with age. For the visual stimulation task, we found age-related changes, with reduced response magnitude with age but no significant effect of APOE allele type. We found no effect of nitrate ingestion on BOLD responses evoked by the breath-hold and visual stimulation tasks. The APOE gene-dependent response to breath-hold may reflect NO-independent differences in vascular function.

Disturbances in the control of capillary flow in an aged APPswe/PS1ΔE9 model of Alzheimer's disease.

Vascular changes are thought to contribute to the development of Alzheimer's disease, and both cerebral blood flow and its responses during neural activation are reduced before Alzheimer's disease symptoms onset. One hypothetical explanation is that capillary dysfunction reduces oxygen extraction efficacy. This study compares the morphology and hemodynamics of the microvasculature in the somatosensory cortex of 18-month-old APPSWE/PS1ΔE9 (transgenic [Tg]) mice and wild-type (WT) littermates. In particular, the extent to which their capillary transit times homogenize during functional activation was measured and compared. Capillary length density was similar in both groups but capillary blood flow during rest was lower in the Tg mice, indicating that cortical oxygen availability is reduced. The capillary hemodynamic response to functional activation was larger, and lasted longer in Tg mice than in WT mice. The homogenization of capillary transit times during functional activation, which we previously demonstrated in young mice, was absent in the Tg mice. This study demonstrates that both neurovascular coupling and capillary function are profoundly disturbed in aged Tg and WT mice.

The effects of transit time heterogeneity on brain oxygenation during rest and functional activation.

The interpretation of regional blood flow and blood oxygenation changes during functional activation has evolved from the concept of 'neurovascular coupling', and hence the regulation of arteriolar tone to meet metabolic demands. The efficacy of oxygen extraction was recently shown to depend on the heterogeneity of capillary flow patterns downstream. Existing compartment models of the relation between tissue metabolism, blood flow, and blood oxygenation, however, typically assume homogenous microvascular flow patterns. To take capillary flow heterogeneity into account, we modeled the effect of capillary transit time heterogeneity (CTH) on the 'oxygen conductance' used in compartment models. We show that the incorporation of realistic reductions in CTH during functional hyperemia improves model fits to dynamic blood flow and oxygenation changes acquired during functional activation in a literature animal study. Our results support earlier observations that oxygen diffusion properties seemingly change during various physiologic stimuli, and posit that this phenomenon is related to parallel changes in capillary flow patterns. Furthermore, our results suggest that CTH must be taken into account when inferring brain metabolism from changes in blood flow- or blood oxygenation-based signals .

In vivo imaging of cerebral serotonin transporter and serotonin(2A) receptor binding in 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and hallucinogen users.

CONTEXT: Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin. OBJECTIVE: To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin(2A) receptor binding. DESIGN: A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 ((11)C)-labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 ((18)F)-labeled altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n = 10) and MDMA-preferring users (n = 14). PARTICIPANTS: Twenty-four young adult users of MDMA and/or hallucinogenic drugs and 21 nonusing controls. MAIN OUTCOME MEASURES: In vivo cerebral SERT and serotonin(2A) receptor binding. RESULTS: Compared with nonusers, MDMA-preferring users showed significant decreases in SERT nondisplaceable binding potential (neocortex, -56%; pallidostriatum, -19%; and amygdala, -32%); no significant changes were seen in hallucinogen-preferring users. Both cortical and pallidostriatal SERT nondisplaceable binding potential was negatively correlated with the number of lifetime MDMA exposures, and the time of abstinence from MDMA was positively correlated with subcortical, but not cortical, SERT binding. A small decrease in neocortical serotonin(2A) receptor binding in the serotonin(2A) receptor agonist users (both user groups) was also detected. CONCLUSIONS: We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin(2A) receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin(2A) agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence.