scholarly journals Quantitative Analysis of Macroscopic Solute Transport in the Murine Brain

2021 ◽  
Author(s):  
Lori A Ray ◽  
Martin Pike ◽  
Matthew Simon ◽  
Jeffrey J Iliff ◽  
Jeffrey J Heys
Keyword(s):  
Quantitative Analysis ◽  
Molecular Transport ◽  
Effective Diffusivity ◽  
Transport Processes ◽  
Interstitial Space ◽  
Perivascular Space ◽  
Transport Parameter ◽  
Transport Parameters ◽  
Dce Mri ◽  
The Brain

Abstract Background: Understanding molecular transport in the brain is critical to care and prevention of neurological disease and injury. A key question is whether transport occurs primarily by diffusion, or also by convection or dispersion. Dynamic contrast-enhanced (DCE) MRI offers a whole-brain view of transport and the potential for quantitative analysis to determine fundamental transport parameters. However, few DCE-MRI studies have utilized this potential, instead reporting parameters with arbitrary units disconnected from fundamental transport processes. Methods: In this work, DCE-MRI experimental data is combined with subject-specific finite-element models to quantify transport parameters in different anatomical regions across the whole mouse brain. Effective diffusivity ( ), a transport parameter combining all mechanisms of transport, is determined for each region by minimizing the root mean square error between simulations and data. The resulting sets are compared to apparent diffusivity ( ) to draw conclusions about dominant transport mechanisms in each region. Results: In the perivascular regions of major arteries, was over 10,000 times greater than . In the brain tissue, constituting interstitial space and the perivascular space of smaller blood vessels, was 10-25 times greater than .Conclusions: The analysis concludes that convection is present throughout the brain. Convection is dominant in the perivascular space of major surface and branching arteries (Pe > 10,000) and significant to large molecules (>1 kDa) in the combined interstitial space and perivascular space of smaller arteries (not resolved by DCE-MRI). Importantly, this work supports periarterial convection along penetrating and smaller arteries.

scholarly journals Quantitative analysis of macroscopic solute transport in the murine brain

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lori A. Ray ◽  
Martin Pike ◽  
Matthew Simon ◽  
Jeffrey J. Iliff ◽  
Jeffrey J. Heys
Keyword(s):  
Experimental Data ◽  
Solute Transport ◽  
Blood Vessels ◽  
Brain Tissue ◽  
Molecular Transport ◽  
Interstitial Space ◽  
Perivascular Space ◽  
Transport Parameter ◽  
Dce Mri ◽  
The Brain

Abstract Background Understanding molecular transport in the brain is critical to care and prevention of neurological disease and injury. A key question is whether transport occurs primarily by diffusion, or also by convection or dispersion. Dynamic contrast-enhanced (DCE-MRI) experiments have long reported solute transport in the brain that appears to be faster than diffusion alone, but this transport rate has not been quantified to a physically relevant value that can be compared to known diffusive rates of tracers. Methods In this work, DCE-MRI experimental data is analyzed using subject-specific finite-element models to quantify transport in different anatomical regions across the whole mouse brain. The set of regional effective diffusivities ($$D_{eff}$$ D eff ), a transport parameter combining all mechanisms of transport, that best represent the experimental data are determined and compared to apparent diffusivity ($$D_{app}$$ D app ), the known rate of diffusion through brain tissue, to draw conclusions about dominant transport mechanisms in each region. Results In the perivascular regions of major arteries, $$D_{eff}$$ D eff for gadoteridol (550 Da) was over 10,000 times greater than $$D_{app}$$ D app . In the brain tissue, constituting interstitial space and the perivascular space of smaller blood vessels, $$D_{eff}$$ D eff was 10–25 times greater than $$D_{app}$$ D app . Conclusions The analysis concludes that convection is present throughout the brain. Convection is dominant in the perivascular space of major surface and branching arteries (Pe > 1000) and significant to large molecules (> 1 kDa) in the combined interstitial space and perivascular space of smaller vessels (not resolved by DCE-MRI). Importantly, this work supports perivascular convection along penetrating blood vessels.

scholarly journals Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 892
Author(s):  
Elisa L. J. Moya ◽  
Elodie Vandenhaute ◽  
Eleonora Rizzi ◽  
Marie-Christine Boucau ◽  
Johan Hachani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Blood Brain Barrier ◽  
Early Stage ◽  
Molecular Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Cns Drugs ◽  
The Impact ◽  
The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

scholarly journals Transport Parameter Correlations for Digitally Created PEFC Gas Diffusion Layers by Using OpenPNM

Processes ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 1141
Author(s):  
Ángel Encalada-Dávila ◽  
Mayken Espinoza-Andaluz ◽  
Julio Barzola-Monteses ◽  
Shian Li ◽  
Martin Andersson
Keyword(s):  
Fuel Cell ◽  
Energy Conversion ◽  
Transport Phenomena ◽  
Electrical Energy ◽  
Gas Diffusion ◽  
Polymer Electrolyte Fuel Cell ◽  
Carbon Paper ◽  
Transport Parameter ◽  
Transport Parameters ◽  
Depth Analysis

A polymer electrolyte fuel cell (PEFC) is an electrochemical device that converts chemical energy into electrical energy and heat. The energy conversion is simple; however, the multiphysics phenomena involved in the energy conversion process must be analyzed in detail. The gas diffusion layer (GDL) provides a diffusion media for reactant gases and gives mechanical support to the fuel cell. It is a complex medium whose properties impact the fuel cell’s efficiency. Therefore, an in-depth analysis is required to improve its mechanical and physical properties. In the current study, several transport phenomena through three-dimensional digitally created GDLs have been analyzed. Once the porous microstructure is generated and the transport phenomena are mimicked, transport parameters related to the fluid flow and mass diffusion are computed. The GDLs are approximated to the carbon paper represented as a grouped package of carbon fibers. Several correlations, based on the fiber diameter, to predict their transport properties are proposed. The digitally created GDLs and the transport phenomena have been modeled using the open-source library named Open Pore Network Modeling (OpenPNM). The proposed correlations show a good fit with the obtained data with an R-square of approximately 0.98.

A finite element model for predicting the distribution of drugs delivered intracranially to the brain

1997 ◽  
Vol 273 (5) ◽  
pp. R1810-R1821 ◽  
Author(s):  
S. Kalyanasundaram ◽  
V. D. Calhoun ◽  
K. W. Leong
Keyword(s):  
Drug Delivery ◽  
Finite Element ◽  
Spin Echo ◽  
Interleukin 2 ◽  
Chemical Species ◽  
Transport Processes ◽  
Proton Density ◽  
Clear Understanding ◽  
Tissue Properties ◽  
The Brain

Drug therapy to the central nervous system is complicated by the presence of the blood-brain barrier. The development of new drug delivery techniques to overcome this obstacle will be aided by a clear understanding of the transport processes in the brain. A rigorous theoretical framework of the transport of drugs delivered locally to the parenchyma has been developed using the finite element method. Magnetic resonance imaging has been used to track the transport of paramagnetic contrast markers in the brain. The information obtained by postprocessing spin-echo, T1-weighted, and proton density images has been used to refine the mathematical model that includes realistic brain geometry and salient anatomic features and allows for two-dimensional transport of chemical species, including both diffusive and convective contributions. In addition, the effects of regional differences in tissue properties, ventricular boundary, and edema on the transport have been considered. The model has been used to predict transport of interleukin-2 in the brain and study the major determinants of transport, at both early and late times after drug delivery.

Analysis of PCO2 differences during rebreathing due to slow pH equilibration in blood

1978 ◽  
Vol 45 (5) ◽  
pp. 666-673 ◽  
Author(s):  
A. Bidani ◽  
E. D. Crandall
Keyword(s):  
Quantitative Analysis ◽  
Gas Exchange ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Transport Processes ◽  
O2 Uptake ◽  
Lung Capillaries ◽  
Mixed Venous ◽  
Co2 Elimination

A quantitative analysis of the reaction and transport processes that occur in blood during and after gas exchange has been used to investigate mechanisms that might account for positive alveolar-mixed venous (A-V) and alveolar-arterial (Aa) PCO2 differences during rebreathing. The analysis was used to determine PCO2 changes that take place in blood as it travels from veins to arteries under conditions in which no CO2 is exchanged in the lung. The predicted A-V and Aa PCO2 differences are all positive and lie within the range of reported measured values. The differences are due to disequilibrium of [H+] between plasma and red blood cells, and to disequilibrium of the reactions CO2 in equilibrium HCO3- + H+ in plasma, as blood leaves the tissue and/or lung capillaries. The differences are increased with exercise and with continued O2 uptake in the lung, the latter due to the Haldane shift. We conclude that the two disequilibria and the Haldane shift contribute to the reported PCO2 differences in rebreathing animals but may not fully account for them. These mechanisms cannot explain any PCO2 differences that might exist during net CO2 elimination from blood in the lung.

General concepts of hypothalamus-pituitary anatomy

2011 ◽  
pp. 71-81
Author(s):  
Ignacio Bernabeu ◽  
Monica Marazuela ◽  
Felipe F. Casanueva
Keyword(s):  
Median Eminence ◽  
Third Ventricle ◽  
Optic Chiasm ◽  
Perivascular Space ◽  
Ependymal Cells ◽  
The Third ◽  
Long Time ◽  
Central Grey Matter ◽  
Imaginary Line ◽  
The Brain

The hypothalamus is the part of the diencephalon associated with visceral, autonomic, endocrine, affective, and emotional behaviour. It lies in the walls of the third ventricle, separated from the thalamus by the hypothalamic sulcus. The rostral boundary of the hypothalamus is roughly defined as a line through the optic chiasm, lamina terminalis, and anterior commissure, and an imaginary line extending from the posterior commissure to the caudal limit of the mamillary body represents the caudal boundary. Externally, the hypothalamus is bounded rostrally by the optic chiasm, laterally by the optic tract, and posteriorly by the mamillary bodies. Dorsolaterally, the hypothalamus extends to the medial edge of the internal capsule (Fig. 2.1.1) (1). The complicated anatomy of this area of the central nervous system (CNS) is the reason why, for a long time, little was known about its anatomical organization and functional significance. Even though the anatomy of the hypothalamus is well established it does not form a well-circumscribed region. On the contrary, it is continuous with the surrounding parts of the CNS: rostrally, with the septal area of the telencephalon and anterior perforating substance; anterolaterally with the substantia innominata; and caudally with the central grey matter and the tegmentum of the mesencephalon. The ventral portion of the hypothalamus and the third ventricular recess form the infundibulum, which represents the most proximal part of the neurohypophysis. A bulging region posterior to the infundibulum is the tuber cinereum, and the zone that forms the floor of the third ventricle is called the median eminence. The median eminence represents the final point of convergence of pathways from the CNS on the peripheral endocrine system and it is supplied by primary capillaries of the hypophyseal portal vessels. The median eminence is the anatomical interface between the brain and the anterior pituitary. Ependymal cells lining the floor of the third ventricle have processes that traverse the width of the median eminence and terminate near the portal perivascular space; these cells, called tanycytes, provide a structural and functional link between the cerebrospinal fluid (CSF) and the perivascular space of the pituitary portal vessels. The conspicuous landmarks of the ventral surface of the brain can be used to divide the hypothalamus into three parts: anterior (preoptic and supraoptic regions), middle (tuberal region), and caudal (mamillary region). Each half of the hypothalamus is also divided into a medial and lateral zone. The medial zone contains the so-called cell-rich areas with well-defined nuclei. The scattered cells of the lateral hypothalamic area have long overlapping dendrites, similar to the cells of the reticular formation. Some of these neurons send axons directly to the cerebral cortex and others project down into the brainstem and spinal cord.

Activity-Related Calcium Dynamics in Motoneurons of the Nucleus Hypoglossus From Mouse

1999 ◽  
Vol 82 (6) ◽  
pp. 2936-2946 ◽  
Author(s):  
Mario B. Lips ◽  
Bernhard U. Keller
Keyword(s):  
Quantitative Analysis ◽  
Action Potential ◽  
Calcium Binding ◽  
Calcium Influx ◽  
Binding Capacity ◽  
Calcium Transients ◽  
Calcium Dynamics ◽  
The Brain

A quantitative analysis of activity-related calcium dynamics was performed in motoneurons of the nucleus hypoglossus in the brain stem slice preparation from mouse by simultaneous patch-clamp and microfluorometric calcium measurements. Motoneurons were analyzed under in vitro conditions that kept them in a functionally intact state represented by rhythmic, inspiratory-related bursts of excitatory postsynaptic currents and associated action potential discharges. Bursts of electrical activity were paralleled by somatic calcium transients resulting from calcium influx through voltage-activated calcium channels, where each action potential accounted for a calcium-mediated charge influx around 2 pC into the somatic compartment. Under in vivo conditions, rhythmic-respiratory activity in young mice occurred at frequencies up to 5 Hz, demonstrating the necessity for rapid calcium elevation and recovery in respiratory-related neurons. The quantitative analysis of hypoglossal calcium homeostasis identified an average extrusion rate, but an exceptionally low endogenous calcium binding capacity as cellular parameters accounting for rapid calcium signaling. Our results suggest that dynamics of somatic calcium transients 1) define an upper limit for the maximum frequency of respiratory-related burst discharges and 2) represent a potentially dangerous determinant of intracellular calcium profiles during pathophysiological and/or excitotoxic conditions.

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