Methods to measure, model and manipulate fluid flow in brain

Abstract

The brain consists of a complex network of cells and matrix that is cushioned and nourished by multiple types of fluids: cerebrospinal fluid, blood, and interstitial fluid. The movement of these fluids through the tissues has recently gained more attention due to implications in Alzheimer's Disease and glioblastoma. Therefore, methods to study these fluid flows are necessary and timely for the current study of neuroscience. Imaging modalities such as magnetic resonance imaging have been used clinically and pre-clinically to image flows in healthy and diseased brains. These measurements have been used to both parameterize and validate models of fluid flow both computational and in vitro. Both of these models can elucidate the changes to fluid flow that occur during disease and can assist in linking the compartments of fluid flow with one another, a difficult challenge experimentally. In vitro models, though in limited use with fluid flow, allow the examination of cellular responses to physiological flow. To determine causation, in vivo methods have been developed to manipulate flow, including both physical and pharmacological manipulations, at each point of fluid movement of origination resulting in exciting findings in the preclinical setting. With new targets, such as the brain-draining lymphatics and glymphatic system, fluid flow and tissue drainage within the brain is an exciting and growing research area. In this review, we discuss the methods that currently exist to examine and test hypotheses related to fluid flow in the brain as we attempt to determine its impact on neural function.

Keywords: Cerebrospinal fluid; Computational modeling; Glymphatic; In vitro models; Interstitial flow; Lymphatics; MRI.

Figure 1:

Location and flow paths of the three main types of fluid flow in brain: cerebrospinal fluid (CSF), interstitial fluid (ISF) and cerebral blood (CB). The CSF originates from the choroid plexus and then flows through the subarachnoid space before draining into the spinal canal, the ISF mainly resides between and around the cells in brain parenchyma and the cerebral blood is mainly present in the intracranial arteries and veins.

Figure 2:

Simplified depiction of glioblastoma microenvironment showing the different types of cells, vasculature and fluid flow that are present. The high pressure inside the tumor results in outward flow of interstitial fluid from the tumor core towards the surrounding matrix which plays a role in the cancer cell invasion.

Figure 3:

Locations and cellular composition of BBB, blood-CSF barrier and CSF – ISF

Figure 4:

A. Schematic and assembled view of Blood Brain Barrier on chip model by (Wang et al., 2017). The side view and the zoomed in panel show the arrangement of cells, porous membrane and the electrical wiring. B. Schematic of the brain on a chip mimicking Alzheimer’s disease by (Park et al., 2015) and the comparison of neurospheroid formation between this device and a normal brain mimicking microfluidic chip. C. Schematic of the interstitial flow chamber and analysis of glioma cell migration under static and flow conditions (Munson et al., 2013).