Vegard Vinje

Fluids and Barriers of the CNS 20 Doi: https://doi.org/10.1186/s12987-023-00459-8

Whether you are reading, running or sleeping, your brain and its fluid environment continuously interacts to distribute nutrients and clear metabolic waste. Yet, the precise mechanisms for solute transport within the human brain have remained hard to quantify using imaging techniques alone. From multi-modal human brain MRI data sets in sleeping and sleep-deprived subjects, we identify and quantify CSF tracer transport parameters using forward and inverse subject-specific computational modelling. Our findings support the notion that extracellular diffusion alone is not sufficient as a brain-wide tracer transport mechanism. Instead, we show that human MRI observations align well with transport by either by an effective diffusion coefficent 3.5 $$\times $$ × that of extracellular diffusion in combination with local clearance rates corresponding to a tracer half-life of up to 5 h, or by extracellular diffusion augmented by advection with brain-wide average flow speeds on the order of 1–9 $$\mu $$ μ m/min. Reduced advection fully explains reduced tracer clearance after sleep-deprivation, supporting the role of sleep and sleep deprivation on human brain clearance.

SIAM Journal on Numerical Analysis 61(3) p. 1449-1481 Doi: https://doi.org/10.1137/21m1449695

We present a new stress/total-pressure formulation for poroelasticity that incorporates the coupling with steady nonlinear diffusion modified by stress. This nonlinear problem is written in mixed-primal form, which combines a perturbed twofold saddle-point system with an elliptic problem. We analyze the continuous formulation within the framework of abstract fixed-point theory and Fredholm alternative for compact operators. A mixed finite element method is proposed, and its stability and convergence are rigorously analyzed. We also provide a few representative numerical examples to illustrate the effectiveness of the proposed formulation. The resulting model can be used to study the steady case of waste removal in the brain, providing insight into the transport of solutes in poroelastic structures under the influence of stress.

PLOS ONE 18(3) Doi: https://doi.org/10.1371/journal.pone.0280501

The glymphatic system is the subject of numerous pieces of research in biology. Mathematical modelling plays a considerable role in this field since it can indicate the possible physical effects of this system and validate the biologists’ hypotheses. The available mathematical models that describe the system at the scale of the brain ( i.e. the macroscopic scale) are often solely based on the diffusion equation and do not consider the fine structures formed by the perivascular spaces. We therefore propose a mathematical model representing the time and space evolution of a mixture flowing through multiple compartments of the brain. We adopt a macroscopic point of view in which the compartments are all present at any point in space. The equations system is composed of two coupled equations for each compartment: One equation for the pressure of a fluid and one for the mass concentration of a solute. The fluid and solute can move from one compartment to another according to certain membrane conditions modelled by transfer functions. We propose to apply this new modelling framework to the clearance of 14 C-inulin from the rat brain.

Fluids and Barriers of the CNS 19:84 p. 1-17 Doi: https://doi.org/10.1186/s12987-022-00376-2

Background Today’s availability of medical imaging and computational resources set the scene for high-fidelity computational modelling of brain biomechanics. The brain and its environment feature a dynamic and complex interplay between the tissue, blood, cerebrospinal fluid (CSF) and interstitial fluid (ISF). Here, we design a computational platform for modelling and simulation of intracranial dynamics, and assess the models’ validity in terms of clinically relevant indicators of brain pulsatility. Focusing on the dynamic interaction between tissue motion and ISF/CSF flow, we treat the pulsatile cerebral blood flow as a prescribed input of the model. Methods We develop finite element models of cardiac-induced fully coupled pulsatile CSF flow and tissue motion in the human brain environment. The three-dimensional model geometry is derived from magnetic resonance images (MRI) and features a high level of detail including the brain tissue, the ventricular system, and the cranial subarachnoid space (SAS). We model the brain parenchyma at the organ-scale as an elastic medium permeated by an extracellular fluid network and describe flow of CSF in the SAS and ventricles as viscous fluid movement. Representing vascular expansion during the cardiac cycle, a prescribed pulsatile net blood flow distributed over the brain parenchyma acts as the driver of motion. Additionally, we investigate the effect of model variations on a set of clinically relevant quantities of interest. Results Our model predicts a complex interplay between the CSF-filled spaces and poroelastic parenchyma in terms of ICP, CSF flow, and parenchymal displacements. Variations in the ICP are dominated by their temporal amplitude, but with small spatial variations in both the CSF-filled spaces and the parenchyma. Induced by ICP differences, we find substantial ventricular and cranial-spinal CSF flow, some flow in the cranial SAS, and small pulsatile ISF velocities in the brain parenchyma. Moreover, the model predicts a funnel-shaped deformation of parenchymal tissue in dorsal direction at the beginning of the cardiac cycle. Conclusions Our model accurately depicts the complex interplay of ICP, CSF flow and brain tissue movement and is well-aligned with clinical observations. It offers a qualitative and quantitative platform for detailed investigation of coupled intracranial dynamics and interplay, both under physiological and pathophysiological conditions.

Frontiers in Bioengineering and Biotechnology 10 p. 1-14 Doi: https://doi.org/10.3389/fbioe.2022.932469

In this paper, we used a computational model to estimate the clearance of a tracer driven by the circulation of cerebrospinal fluid (CSF) produced in the choroid plexus (CP) located within the lateral ventricles. CSF was assumed to exit the subarachnoid space (SAS) via different outflow routes such as the parasagittal dura, cribriform plate, and/or meningeal lymphatics. We also modelled a reverse case where fluid was produced within the spinal canal and absorbed in the choroid plexus in line with observations on certain iNPH patients. No directional interstitial fluid flow was assumed within the brain parenchyma. Tracers were injected into the foramen magnum. The models demonstrate that convection in the subarachnoid space yields rapid clearance from both the SAS and the brain interstitial fluid and can speed up intracranial clearance from years, as would be the case for purely diffusive transport, to days.

Scientific Reports 11(1) Doi: https://doi.org/10.1038/s41598-021-95306-x

Fluid flow in perivascular spaces is recognized as a key component underlying brain transport and clearance. An important open question is how and to what extent differences in vessel type or geometry affect perivascular fluid flow and transport. Using computational modelling in both idealized and image-based geometries, we study and compare fluid flow and solute transport in pial (surface) periarterial and perivenous spaces. Our findings demonstrate that differences in geometry between arterial and venous pial perivascular spaces (PVSs) lead to higher net CSF flow, more rapid tracer transport and earlier arrival times of injected tracers in periarterial spaces compared to perivenous spaces. These findings can explain the experimentally observed rapid appearance of tracers around arteries, and the delayed appearance around veins without the need of a circulation through the parenchyma, but rather by direct transport along the PVSs.

Brain 144(3) p. 863-874 Doi: https://doi.org/10.1093/brain/awaa443

International Journal for Numerical Methods in Biomedical Engineering 37(1)

PLOS ONE 15(12) Doi: https://doi.org/10.1371/journal.pone.0244442

Flow of cerebrospinal fluid (CSF) in perivascular spaces (PVS) is one of the key concepts involved in theories concerning clearance from the brain. Experimental studies have demonstrated both net and oscillatory movement of microspheres in PVS (Mestre et al. (2018), Bedussi et al. (2018)). The oscillatory particle movement has a clear cardiac component, while the mechanisms involved in net movement remain disputed. Using computational fluid dynamics, we computed the CSF velocity and pressure in a PVS surrounding a cerebral artery subject to different forces, representing arterial wall expansion, systemic CSF pressure changes and rigid motions of the artery. The arterial wall expansion generated velocity amplitudes of 60–260 μ m/s, which is in the upper range of previously observed values. In the absence of a static pressure gradient, predicted net flow velocities were small (<0.5 μ m/s), though reaching up to 7 μ m/s for non-physiological PVS lengths. In realistic geometries, a static systemic pressure increase of physiologically plausible magnitude was sufficient to induce net flow velocities of 20–30 μ m/s. Moreover, rigid motions of the artery added to the complexity of flow patterns in the PVS. Our study demonstrates that the combination of arterial wall expansion, rigid motions and a static CSF pressure gradient generates net and oscillatory PVS flow, quantitatively comparable with experimental findings. The static CSF pressure gradient required for net flow is small, suggesting that its origin is yet to be determined.

Fluids and Barriers of the CNS 17(29) Doi: https://doi.org/10.1186/s12987-020-00189-1

Background Infusion testing is a common procedure to determine whether shunting will be beneficial in patients with normal pressure hydrocephalus. The method has a well-developed theoretical foundation and corresponding mathematical models that describe the CSF circulation from the choroid plexus to the arachnoid granulations. Here, we investigate to what extent the proposed glymphatic or paravascular pathway (or similar pathways) modifies the results of the traditional mathematical models. Methods We used a compartment model to estimate pressure in the subarachnoid space and the paravascular spaces. For the arachnoid granulations, the cribriform plate and the glymphatic circulation, resistances were calculated and used to estimate pressure and flow before and during an infusion test. Finally, different variations to the model were tested to evaluate the sensitivity of selected parameters. Results At baseline intracranial pressure (ICP), we found a very small paravascular flow directed into the subarachnoid space, while 60% of the fluid left through the arachnoid granulations and 40% left through the cribriform plate. However, during the infusion, 80% of the fluid left through the arachnoid granulations, 20% through the cribriform plate and flow in the PVS was stagnant. Resistance through the glymphatic system was computed to be 2.73 mmHg/(mL/min), considerably lower than other fluid pathways, giving non-realistic ICP during infusion if combined with a lymphatic drainage route. Conclusions The relative distribution of CSF flow to different clearance pathways depends on ICP, with the arachnoid granulations as the main contributor to outflow. As such, ICP increase is an important factor that should be addressed when determining the pathways of injected substances in the subarachnoid space. Our results suggest that the glymphatic resistance is too high to allow for pressure driven flow by arterial pulsations and at the same time too small to allow for a direct drainage route from PVS to cervical lymphatics.

Scientific Reports 9 p. 1-13 Doi: https://doi.org/10.1038/s41598-019-46055-5

Current theories suggest that waste solutes are cleared from the brain via cerebrospinal fluid (CSF) flow, driven by pressure pulsations of possibly both cardiac and respiratory origin. In this study, we explored the importance of respiratory versus cardiac pressure gradients for CSF flow within one of the main conduits of the brain, the cerebral aqueduct. We obtained overnight intracranial pressure measurements from two different locations in 10 idiopathic normal pressure hydrocephalus (iNPH) patients. The resulting pressure gradients were analyzed with respect to cardiac and respiratory frequencies and amplitudes (182,000 cardiac and 48,000 respiratory cycles). Pressure gradients were used to compute CSF flow in simplified and patient-specific models of the aqueduct. The average ratio between cardiac over respiratory flow volume was 0.21 ± 0.09, even though the corresponding ratio between the pressure gradient amplitudes was 2.85 ± 1.06. The cardiac cycle was 0.25 ± 0.04 times the length of the respiratory cycle, allowing the respiratory pressure gradient to build considerable momentum despite its small magnitude. No significant differences in pressure gradient pulsations were found in the sleeping versus awake state. Pressure gradients underlying CSF flow in the cerebral aqueduct are dominated by cardiac pulsations, but induce CSF flow volumes dominated by respiration.

The Neuroradiology Journal (NRJ) 31(5) p. 482-489 Doi: https://doi.org/10.1177/1971400918795482

Skolebasert kompetanseutvikling - organisasjonslæring for delingskultur p. 127-141

International congress on industrial and applied mathematics, Valencia, Spain

Phase contrast MRI does not take into account the role of respiration on cerebrospinal fluid (CSF) flow. We used in vivo pressure measurements from two locations in the intracranial space to calculate a pulsatile pressure gradient. This pressure data was used as input to an idealized model of the aqueduct to calculate CSF flow. We found the cardiac and respiratory cycle to contribute equally to CSF flow. The total flow volume was dominated by respiration, and all subjects showed variability in pressure gradients over time resulting also in variability in CSF flow.

Glasgow, United Kingdom

Vancouver, Canada

Hamburg, Germany

This talk presents a general overview of the numerical work at the Waterscape group at Simula. First, I present the governing equations, together with standard solving schemes and how to handle discretization in FEniCS. The total pressure formulation is introduced, and an optimal preconditioner for the total pressure formulation is presented.In the last five-ten years, fluid flow and solute transport in the human brain has gained rapid interest in the research community. The discoveries by Iliff and Nedergaard describing a glyphatic network washing solutes out of the brain through a bulk flow of fluid, followed by Xie et al.'s study claiming that sleep enhances this mechanism was discoveries that also gained significant media attention.The brain has several more or less separated networks allowing for fluid flow; Blood vessels, paravascular spaces and interstitial fluid. The relation between fluid flow in these networks to each other and to the macroscoping displacement of brain tissue can be explained with the multiple network poroelastic theory (MPET). Because there are no consensus of the value of all material parameters the models we use need to be robust within a given parameter regime. In addition, as the number of networks grow, the system of equations becomes larger and the solvers we use must also be fast and efficient within the given range of the parameters.The total pressure formulation, presented in this talk, restores convergence related to the problem of "locking", and allows for a parameter robust preconditioner. Proof that the scheme is stable has been given earlier, and the current work aims to extend this proof to a general number of networks.

International Convention Center, Kobe, Japan

Recent studies using magnetic resonance imaging (MRI) have suggested cerebrospinal fluid (CSF) motion caused by respiration to play a more important role than previously thought. The cardiac cycle of CSF motion is used clinically, often to predict which hydrocephalus patients will respond to shunting and who will not.This talk asks the question whether CSF flow could also be regulated by the longer respiratory cycle. To assess this question we applied in vivo pressure measurements to a simplification of the spinal canal and the aqueduct. From this we can measure the amplitude of the flow components induced by the cardiac and respiratory cycle respectively.In our study the amplitude of CSF motion was higher for respiration in the spinal canal, and in the aqueduct cardiac the two amplitudes were approximately equal.This is a starting work, so no conclusions can be made yet. We emphasize the point that it is possible for small and long pressure waves in respiration to cause greater flow than a short cardiac pressure wave with a greater amplitude.