We recently extended the classic flow-diffusion equation, which relates blood flow to tissue oxygenation, to take capillary transit time heterogeneity (CTH) into account. Realizing that cerebral oxygen availability depends on both cerebral blood flow (CBF) and capillary flow patterns, we have speculated that CTH may be actively regulated and that changes in the capillary morphology and function, as well as in blood rheology, may be involved in the pathogenesis of conditions such as dementia and ischemia-reperfusion injury. The first extended flow-diffusion equation involved simplifying assumptions which may not hold in tissue. Here, we explicitly incorporate the effects of oxygen metabolism on tissue oxygen tension and extraction efficacy, and assess the extent to which the type of capillary transit time distribution affects the overall effects of CTH on flow-metabolism coupling reported earlier. After incorporating tissue oxygen metabolism, our model predicts changes in oxygen consumption and tissue oxygen tension during functional activation in accordance with literature reports. We find that, for large CTH values, a blood flow increase fails to cause significant improvements in oxygen delivery, and can even decrease it; a condition of malignant CTH. These results are found to be largely insensitive to the choice of the transit time distribution.

Functional hyperemia reduces oxygen extraction efficacy unless counteracted by a reduction of capillary transit-time heterogeneity of blood. We adapted a bolus tracking approach to capillary transit-time heterogeneity estimation for two-photon microscopy and then quantified changes in plasma mean transit time and capillary transit-time heterogeneity during forepaw stimulation in anesthetized mice (C57BL/6NTac). In addition, we analyzed transit time coefficient of variance = capillary transit-time heterogeneity/mean transit time, which we expect to remain constant in passive, compliant microvascular networks. Electrical forepaw stimulation reduced, both mean transit time (11.3% ± 1.3%) and capillary transit-time heterogeneity (24.1% ± 3.3%), consistent with earlier literature and model predictions. We observed a coefficient of variance reduction (14.3% ± 3.5%) during functional activation, especially for the arteriolar-to-venular passage. Such coefficient of variance reduction during functional activation suggests homogenization of capillary flows beyond that expected as a passive response to increased blood flow by other stimuli. This finding is consistent with an active neurocapillary coupling mechanism, for example via pericyte dilation. Mean transit time and capillary transit-time heterogeneity reductions were consistent with the relative change inferred from capillary hemodynamics (cell velocity and flux). Our findings support the important role of capillary transit-time heterogeneity in flow-metabolism coupling during functional activation.

Magnetic resonance imaging has proved to be suitable and efficient for in vivo investigation of the early process of brain gyrification in fetuses and preterm newborns but the question remains as to whether cortical-related measurements derived from both cases are comparable or not. Indeed, the developmental folding trajectories drawn up from both populations have not been compared so far, neither from cross-sectional nor from longitudinal datasets. The present study aimed to compare features of cortical folding between healthy fetuses and early imaged preterm newborns on a cross-sectional basis, over a developmental period critical for the folding process (21-36 weeks of gestational age [GA]). A particular attention was carried out to reduce the methodological biases between the 2 populations. To provide an accurate group comparison, several global parameters characterizing the cortical morphometry were derived. In both groups, those metrics provided good proxies for the dramatic brain growth and cortical folding over this developmental period. Except for the cortical volume and the rate of sulci appearance, they depicted different trajectories in both groups suggesting that the transition from into ex utero has a visible impact on cortical morphology that is at least dependent on the GA at birth in preterm newborns.

Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.

Ischemic heart disease (IHD) is characterized by an imbalance between oxygen supply and demand, most frequently caused by coronary artery disease (CAD) that reduces myocardial perfusion. In some patients, IHD is ascribed to microvascular dysfunction (MVD): microcirculatory disturbances that reduce myocardial perfusion at the level of myocardial pre-arterioles and arterioles. In a minority of cases, chest pain and reductions in myocardial flow reserve may even occur in patients without any other demonstrable systemic or cardiac disease. In this topical review, we address whether these findings might be caused by impaired myocardial oxygen extraction, caused by capillary flow disturbances further downstream. Myocardial blood flow (MBF) increases approximately linearly with oxygen utilization, but efficient oxygen extraction at high MBF values is known to depend on the parallel reduction of capillary transit time heterogeneity (CTH). Consequently, changes in capillary wall morphology or blood viscosity may impair myocardial oxygen extraction by preventing capillary flow homogenization. Indeed, a recent re-analysis of oxygen transport in tissue shows that elevated CTH can reduce tissue oxygenation by causing a functional shunt of oxygenated blood through the tissue. We review the combined effects of MBF, CTH, and tissue oxygen tension on myocardial oxygen supply. We show that as CTH increases, normal vasodilator responses must be attenuated in order to reduce the degree of functional shunting and improve blood-tissue oxygen concentration gradients to allow sufficient myocardial oxygenation. Theoretically, CTH can reach levels such that increased metabolic demands cannot be met, resulting in tissue hypoxia and angina in the absence of flow-limiting CAD or MVD. We discuss these predictions in the context of MVD, myocardial infarction, and reperfusion injury.

In the human brain, the appearance of cortical sulci is a complex process that takes place mostly during the second half of pregnancy, with a relatively stable temporal sequence across individuals. Since deviant gyrification patterns have been observed in many neurodevelopmental disorders, mapping cortical development in vivo from the early stages on is an essential step to uncover new markers for diagnosis or prognosis. Recently this has been made possible by MRI combined with post-processing tools, but the reported results are still fragmented. Here we aimed to characterize the typical folding progression ex utero from the pre- to the post-term period, by considering 58 healthy preterm and full-term newborns and infants imaged between 27 and 62 weeks of post-menstrual age. Using a method of spectral analysis of gyrification (SPANGY), we detailed the spatial-frequency structure of cortical patterns in a quantitative way. The modeling of developmental trajectories revealed three successive waves that might correspond to primary, secondary and tertiary folding. Some deviations were further detected in 10 premature infants without apparent neurological impairment and imaged at term equivalent age, suggesting that our approach is sensitive enough to highlight the subtle impact of preterm birth and extra-uterine life on folding.

Cerebral ischemia causes widespread capillary no-flow in animal studies. The extent of microvascular impairment in human stroke, however, is unclear. We examined how acute intra-voxel transit time characteristics and subsequent recanalization affect tissue outcome on follow-up MRI in a historic cohort of 126 acute ischemic stroke patients. Based on perfusion-weighted MRI data, we characterized voxel-wise transit times in terms of their mean transit time (MTT), standard deviation (capillary transit time heterogeneity - CTH), and the CTH:MTT ratio (relative transit time heterogeneity), which is expected to remain constant during changes in perfusion pressure in a microvasculature consisting of passive, compliant vessels. To aid data interpretation, we also developed a computational model that relates graded microvascular failure to changes in these parameters. In perfusion-diffusion mismatch tissue, prolonged mean transit time (>5 seconds) and very low cerebral blood flow (≤6 mL/100 mL/min) was associated with high risk of infarction, largely independent of recanalization status. In the remaining mismatch region, low relative transit time heterogeneity predicted subsequent infarction if recanalization was not achieved. Our model suggested that transit time homogenization represents capillary no-flow. Consistent with this notion, low relative transit time heterogeneity values were associated with lower cerebral blood volume. We speculate that low RTH may represent a novel biomarker of penumbral microvascular failure.

In 1919, August Krogh published his seminal work on skeletal muscle oxygenation. Krogh’s observations indicated that muscle capillary diameter is actively regulated, rather than a passive result of arterial blood flow regulation. Indeed, combining a mathematical model with the number of ink-filled capillaries he observed in muscle cross sections taken at different workloads, Krogh was able to account for muscle tissue’s remarkably efficient oxygen extraction during exercise in terms of passive diffusion from nearby capillaries. Krogh was awarded the 1920 Nobel Prize for his account of muscle oxygenation. Today, his observations are engrained in the notion of capillary recruitment: the opening of previously closed capillaries. While the binary distinction between “closed” and “open” was key to Krogh’s model argument, he did in fact report a continuum of capillary diameters, degrees of erythrocyte deformation, and perfusion states. Indeed, modern observations question the presence of closed muscle capillaries. We therefore examined whether changes in capillary flow patterns and hematocrit among open capillaries can account for oxygen extraction in muscle across orders-of-magnitude changes in blood flow. Our four-compartment model of oxygen extraction in muscle confirms this notion and provides a framework for quantifying the impact of changes in microvascular function on muscle oxygenation in health and disease. Our results underscore the importance of capillary function for oxygen extraction in muscle tissue as first proposed by Krogh. While Krogh’s model calculations still hold, our model predictions support that capillary recruitment can be viewed in the context of continuous, rather than binary, erythrocyte distributions among capillaries. NEW & NOTEWORTHY Oxygen extraction in working muscle is extremely efficient in view of single capillaries properties. The underlying mechanisms have been widely debated. Here, we develop a four-compartment model to quantify the influence of each of the hypothesized mechanisms on muscle oxygenation. Our results show that changes in capillary flow pattern and hematocrit can account for the high oxygen extraction observed in working muscle, while capillary recruitment is not required to account for these extraction properties.