Basic CNS Fluid Physiology

Andreas A Linninger¹

¹United States

Synopsis

Keywords: cerebrospinal fluid flow, intrathecal drug delivery, intracranial dynamics,

Target Audience

MRI physicists, biomedical engineers, mathematicians, computer scientists, as well as scientists interested in pharmacokinetics and pharmacodynamics of CSF, physiologists, neurologists and neurosurgeons

Outcomes/Objectives

Overview of CSF physiology and intracranial dynamics

Purpose

· Provide an overview and update on recent development in characterization and imaging of CSF motion

· Illustrate open research questions regarding CSF motion induced transport

Methods/Results

Imaging and research data will be used to eluciate basic anatomy of CSF filled space and natural movement of CSF. Open research questions regarding the physiological connection between CSF and ISF will be posed.

CSF Motion in the Cranium

The brain and spinal cord are surrounded by CSF, a clear fluid with a density and viscosity close to water. It fills the ventricular system and the cranial and spinal SAS. CSF inside the CNS does not remain stagnant but pulsates ¹. CSF also flows from the cranial to the spinal SAS in systole, with flow reversal from the spinal SAS into the cranium in diastole. A respiratory influence on the CSF oscillations in the aqueduct has also been observed^2–7. The exact source location and type of force coupling between the expanding and contracting vasculature, brain movement and induced CSF dynamics are still uncertain. Because the human CNS seems to lack a classical lymphatic system, CSF clearance differs from peripheral extracellular fluid drainage. CSF is believed to be reabsorbed into the venous system through the arachnoid villi, protrusions of the arachnoid membrane into the superior sagittal sinus, located (Figure 1a) or alternatively though nerve paths into the extracranial lymphatic system. Animal experiments suggest that lymphatic drainage is significant in rodents^8,9and dogs⁹. Recent findings point toward the existence of a meningeal lymphatic network in mice¹⁰. However, the extent of lymphatic drainage in humans is still debated^11,12. Alternative theories of CSF production and reabsorption question this traditional view of CSF production ^13–16. Supported by dilution experiments in cats, Klarica et al. (2005) proposed the theory that CSF production and reabsorption occur throughout the parenchyma without a clear bulk component due to choroidal production or clearance through arachnoid villi.

Interstitial fluid dynamics.

The traditional view also holds that a fraction of CSF is secreted from the brain tissue, which is in agreement with Klarica et al.’s theory ^17–19. New data suggest that the brain actively regulates the size of the ECS in accordance with metabolic needs ²⁰. In addition to the possibility of fluid generation inside the tissue, ICF reabsorption from the interstitium into the microvasculature has been proposed as a way to interpret brain water content changes²¹. Experimental evidence also suggests the notion of net flow of CSF into the interstitial brain tissue ²². Several studies show that CSF can exit the ventricles under high pressure ^23–25. Transependymal flow into perivascular spaces may be significant in hydrocephalus ²⁶. Furthermore, the role of osmolarity exercising Starling forces needs to be quantified to determine the amount and directionality of bulk water exchange across the blood-brain barrier ²⁷. Water exchange from astrocytic endfeet (Figure 1b) into the ECS sparked a growing interest in transmembrane proteins known as aquaporin channels ^28–31. Despite these developments, a high degree of uncertainty about the amount, direction, and physiochemical driving forces of interstitial fluid exchange remains.

Cerebrospinal Fluid Flow of the Spine.

In normal humans, 0.5-2 mL of CSF are displaced into the cervical SAS during systole in each cardiac cycle and flow back into the cranial SAS during diastole. Four-dimensional (4D) magnetic resonance measurements show a sharp CSF pulse shooting from the prepontine area into the cervical SAS ³². Additionally, flow velocities are higher in the anterior cervical SAS, with concentrated jets propagating along the cervical region. Craniocaudal flow into the spinal SAS requires concomitant expansions of the fluid-filled spaces. The systolic CSF inflow into the spinal SAS is believed to be accommodated by the deformation of the dura membrane, which in turn is enabled by displacement of venous blood or the compression of fatty epidural tissue especially in the lumbar region ^33,34. PC MRI velocity measurements depict a gradual decline in the CSF stroke volume when measured at descending locations from the cervical to the lumbar spine. In addition to volumetric flow rate peak amplitude attenuation, a gradual increment in the phase lag of the velocity maximum was observed ³⁵. Measured peak amplitude attenuation and phase lags were used to infer the volumetric strains responsible for spinal compliance ³⁶. More precise measurements of the velocity waves and their timing are expected to localize and quantify the spatial extent of spinal dura deformations. The spinal CSF flow experiences intricate geometry-induced microflow patterns due to microanatomical aspects that can be found in the SAS (Figure 1c--e). Microanatomical features causing complex flows include ligaments, nerve roots, trabeculae, meningeal layers, and spinal white matter and gray matter, which have been carefully characterized by Reina et al. (2002a,b, 2004, 2015). Several groups are beginning to clarify the role of nerve roots on the geometry-induced CSF flow patterns in the spine^{37 36,38,39}.

Discussion

Research into CSF dynamics is an active field of research. Knowledge about CSF-ISF pathways is significant for a basic understanding of brain clearance functions that have relevance in brain pathologies (AD, Parkinsons). Moreover quantification of CSF dynamics is necessary for determining the driving forces of drug transport in non-invasive drug delivery modalities. These include intra-ventricular, intra-thecal and intra-parenchmal delivery options. Since many active drug molecules cannot cross the blood brain barrier, the significance of invasive drug delivery methods is expected to gain in importance.

Conclusion

The overview raised open research questions as follows:

· What are the physiological connections between CSF and ISF.

· How are the fundamental mechanism of water homeostasis between the vascular and extravascular compartments? How is water exchanged in different brain compartments during awake and sleep stares as well as in normal and pathologies.

· What are physiological pathways and the fluid flows that are carried along lymph-like conduits along the venous sinuses that allow fluid to leave the cranial subarachnoid space without passing through the subarachnoid villi

· How are perivascular spaces connected to the lymph-like conduits

Acknowledgements

No acknowledgement found.

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Figures

Anatomical diagram of the main structures in the central nervous system reconstructed from a subject-specific MRI; adapted from Linninger et al. 2015.The full extent of the spinal and cranial space is shown to the left.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)