Recent advances in scientific methodology and experimentation have proven to be effective tools for elucidating the mechanisms of the CSF circulation system and the pathological conditions associated with its malfunction. In this review, we capitulate the classical understanding of CSF physiology as well as a new, emerging theory on CSF production. Cerebrospinal fluid CSF is a clear, proteinaceous fluid that exists in the surrounding spaces of mammalian central nervous systems CNS.
It is a multifaceted marvel, able to continuously support the nervous system through the lifespan of the organism. In the average adult human, there is roughly mL of CSF circulating at any given moment. CSF forms at a rate of about 0. In this review, we will outline the physiology of CSF in the typical adult, as well as the pathologies associated with CSF circulation, malabsorption, and production. The existence of CSF has been known for centuries.
Hippocrates was among the first to describe the fluid as water that surrounded the brain. Since then, this theory has been taken as fact, and many studies conducted on the choroid plexus and CSF secretion have revolved around this concept.
The secretion of CSF from any of the four choroid plexuses occurs as a two-stage process. The ultrafiltrate then undergoes active transport across the choroidal epithelium into the ventricular spaces.
They call into question nearly years of research which elucidated the role of the plexuses in the CSF system, citing faulty methodologies that are highly subject to error and misinterpretation as well as experimental settings ex vivo and in vitro that do not represent the true physiology of the system.
The authors assert that no experiment has undoubtedly confirmed the capacity of the choroid plexus to completely generate the predicted volume of CSF. The main criticism asserted is that Dandy's previously mentioned experiment was not reproducible and conducted on only a single canine subject, yet served as a foundation for the classical theory.
The new working theory they posit sees CSF formation as an active process that is not affected by intracranial pressure. In balanced physiological conditions, the rate of CSF formation must be equal to the rate of absorption. They postulate that this could extend to flow rate, given that formation and absorption occur in different compartments of the system.
To them, it is, therefore, logical to say that secretion of CSF is the driving force of flow and circulation if there is going to be a steady volume of CSF.
According to the classical theory, a choroid plexectomy should significantly reduce the overall secretion of CSF, therefore providing some pressure relief in patients who have hydrocephalus.
However, this is not always the outcome of the procedure; in fact, research shows that two-thirds of patients who receive the treatment should be shunted due to the recurrence of hydrocephalus. The new theory takes a more systematic approach, it shifts attention to the Virchow—Robin spaces also known as perivascular spaces , which exist between where the cerebral vasculature descends from the subarachnoid space into the CNS, perforating the pia mater.
This would indicate that CSF is continually produced throughout the circulatory route and not in localized secretory organs, and any changes in the volume of CSF are influenced by the CSF osmolarity.
While there is evidence to support these claims of CSF mixing and production, there is also a wealth of literature describing the ebbs and flows of CSF, and net flow. The composition of CSF varies from that of serum due to the differential expression of membrane-associated channels and transport proteins, ultimately resulting in the unidirectional nature of the choroidal epithelium. Compared to plasma, CSF generally contains a higher concentration of sodium, chloride, and magnesium and lower concentrations of potassium and calcium.
Movement of water across the apical membrane has been shown to be due to the presence of aquaporin-1 AQ-1 ; in fact, a study conducted by Mobasheri and Marples revealed that choroid plexus was among the tissues with the highest expression of AQ-1 in the body. The function of CSF has been one focus of mechanistic study, and the study of disease states which influence production, absorption, or CSF composition. Similarly, the microenvironment composition surrounding periventricular cells, and their activity, are manipulated by changes in solute transporters and CSF pathologies.
After production, CSF movement generally occurs through the ventricular system, assisted, in part, by ciliated ependyma which beat in synchrony. Next, it flows through the aqueduct of Sylvius into the fourth ventricle. From the fourth ventricle, the CSF may exit through the foramen of Lushka laterally, or the foramen of Magendie medially to the subarachnoid space.
Passing through the foramen of Magendie results in filling of the spinal subarachnoid space. CSF egressing through the foramen of Lushka travels into the subarachnoid space of the cisterns and subarachnoid space overlying the cerebral cortex. The CSF from the subarachnoid space is eventually reabsorbed through outpouchings into the superior sagittal sinus SSS known as the arachnoid granulations. Arachnoid granulations act as an avenue for CSF reabsorption into the blood circulation through a pressure-dependent gradient.
This conclusion was derived from in vivo two-photon laser scanning microscopy, fluorescent microscopy and measurements of the ISF volume comparing awake, asleep and anaesthesized animals. However, again, this is a very complex study design possibly prone to experimental errors: investigating animals with multiple brain catheters and fixated in a stereotactic or microscopic holder, one may assume that awake animals are under massive stress and may fell asleep just because of exhaustion.
Although microdialysis was used to measure norepinephrine levels as a gauge for stress levels and norepinephrine did not increase in the experiments, important stress parameters may differ between the experimental groups, i. The fact that none of these parameters was recorded during the experiments is a major drawback, since each of the parameters may alter cerebral blood flow, cerebral blood volume, intracranial pressure and even the perivascular pump[ 79 ].
In spite of this criticism, the observation that astrocytes are involved in the clearance of interstitial waste molecules including soluble amyloid is exciting. In this regard the experiments of Iliff et al. Confirmatory evidence of the impact of aquaporins on ISF regulation has been independently reported by others[ ]. The new findings do not render all of the previous, sometimes historical, work invalid.
However, CSF researchers and clinicians have to recognize that much of the earlier findings need to be re-interpreted. For example, the discovery of aquaporins and other water transporters, all highly selective just for water molecules, implies that the extent of water exchange across the barriers may be heavily underestimated by the classical flow studies[ 30 , 49 ].
The tracers, used in the classical experiments, were always larger than water molecules and therefore could not be a substrate for the water transporters. Also, the notion that osmolality does not impact CSF absorption[ 2 , 33 ] or that CSF absorption into capillaries requires a hydraulic pressure gradient, which would cause the collapse of the vessel[ 47 ], needs to be reconsidered.
Even more puzzling, the notion of directed bulk flow movement of CSF, i. As already suggested by others[ 9 , ], the novel findings indicate that CSF circulation is much more complex, a combination of directed bulk flow, pulsatile to and fro movement, and continuous bi-directional fluid exchange at the blood brain barrier and the cell membranes at the borders between CSF and ISF spaces. Ongoing research emphasizes the role of lymphatic pathways for the drainage of ISF and CSF[ 45 ]; the observation that astrocytes and their aquaporins drive lymphatic drainage may open a new field of research[ 95 ].
The new insights into the physiology of CSF circulation may have important clinical relevance for example for the understanding of neurodegenerative and immunological diseases of the brain[ 45 , ]. Also, opposing the classical view that drugs injected into the CSF space will be washed out within short time without targeting the brain[ 5 ], recent findings demonstrate that drugs, following intrathecal application, may very well be transported throughout the entire brain[ ].
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J Neurosci. Zelenina M: Regulation of brain aquaporins. Biochim Biophys Acta. J Cereb Blood Flow Metab. Agre P: The aquaporin water channels. Proc Am Thorac Soc. In addition, any increase in intraventricular pressure can reduce plasma filtration and, as a result, CSF production by lowering the pressure gradient in the blood—brain barrier. In CSF and interstitial brain fluid, water and solutes change constantly, and this balance provides an optimal environment for neurons. In aging, there is less efficient active transport, with a slower CSF cycle causing the accumulation of potentially harmful metabolites in the interstitium of the brain.
Clearance of brain metabolites per minute depends on the CSF regeneration at a rate of 0. After production, CSF movement is usually carried out through the ventricular system, while it is also supported by the cilia ependyma [ 23 ]. The net flow of the CSF passes through the ventricular system, starting from the lateral ventricles [ 24 ]. The CSF flows from the lateral ventricles, through the left and right foramen of the Monro to the third ventricle.
Then, it passes to the 4th ventricles. From the fourth ventricle, the CSF may flow laterally from the foramen of Lushka, or medially from the foramen of Magendie to the subarachnoid space. Passing through the foramen of Magendie results in the filling of the spinal subarachnoid space. CSF outflow from the foramen of Luschka goes into the subarachnoid space of cisterns and into the subarachnoid space that covers the cerebral cortex.
CSF from the subarachnoid space is eventually reabsorbed into the superior sagittal sinus SSS , known as the arachnoid. Arachnoid granulations provide reabsorption of CSF into the bloodstream by a pressure-dependent gradient [ 6 ].
In arachnoid granulations, outlets towards the CNS are seen due to the fact that the pressure in the subarachnoid space is greater than the venous sinus pressure. Similar to new theories about CSF production, there are also absorption theories.
Studies in animal models have revealed that CSF can also be significantly absorbed through cervical lymphatics [ 6 ]. CSF, which is not reabsorbed by arachnoid granulations, can reach cervical lymphatics in two alternative ways.
The first is along the subarachnoid space of the emerging cranial nerves [ 6 ]. This provides a direct route through which CSF can be transferred from cisterns to extracranial lymphatics. The second way in which CSF can reach lymphatics is through the Virchow-Robin space of the arteries and veins that penetrate the parenchyma of the brain [ 25 ]. The Virchow-Robin Space VRS is the area surrounding the arteries and veins of the brain parenchyma, which can vary in size depending on disease status.
In addition to the circulation of CSF to cervical lymphatics, studies have also been conducted explaining the reabsorption of CSF to the dural venous plexus. Arachnoid granulations at birth are not fully developed, and CSF absorption is based on the venous plexus of the inner surface of dura, which is more robust in infants [ 26 ]. Although not common in adults, the dural venous plexus is believed to play a role in absorption. Adult and fetal cadaver dissections and animal models with intradural injection have all been shown to fill the parasagittal dural venous plexus [ 27 ].
The CSF physiology, in the classical sense, is based mainly on animal experiments [ 28 ]. In recent research, the structure of CSF circulation has been questioned, challenging significant aspects of the classical model. Recently, CSF production and absorption have been reevaluated [ 9 , 29 , 30 , 31 ].
The CSF then continues to flow either downwards around the spinal cord or upwards over the cerebral convexities, and is eventually absorbed by arachnoid granulations and arachnoidal villi on either side of the upper sagittal sinus. Recent studies have highlighted a secondary pathway of CSF, circulation through perivascular VRS, similar to the lymphatic system in other parts of the body [ 34 , 35 ]. The glial membrane of the brain consists of the astrocytic end-feet and forms theVRS, it has high amounts of aquaporin channels and facilitates CSF transfer from VRS to the interstitial space of the brain cavity is cleaned and then empty the drainage paths paravenous makes it easy to carry along [ 36 ].
The in vivo imaging taken using fluorescent substances in mice also showed how this microcirculation removes amyloid beta and other waste products from the central nervous system [ 34 ]. CSF flow is pulsatile and depends on pulsational arterial perfusion. A central ventricular pulse wave is formed, followed by brain expansion, followed by a subarachnoid CSF frontooccipital pulse wave [ 38 ].
During systole, blood flows into the brain, expanding into the brain, compressing the ventricles and the cortical vessels outwards and SAS. Inward expansion of the brain leads to the pulsatile transfer of CSF from the the cerebral aqueduct and the rest of the ventricular system. During diastole, the volume of the brain decreases, and CSF flows in the opposite direction along the the cerebral aqueduct and the foramen magnum. Although in-vivo studies in humans are needed to confirm these findings, there is growing evidence that plaque may be another key site for extracranial output [ 24 , 39 ].
Since Cushing, the collective flow character of CSF circulation has been accepted by most researchers. In some cases, hydrocephalus can develop when the choroid plexus produces too much CSF.
This can happen when there is a tumor on the choroid plexus, for example. CSF flows from the lateral ventricles through two narrow passageways into the third ventricle.
From the third ventricle, it flows down another long passageway known as the aqueduct of Sylvius into the fourth ventricle. From the fourth ventricle, it passes through three small openings called foramina and into the subarachnoid space surrounding the brain and the spinal cord. If the flow of CSF at any of these points is blocked, hydrocephalus can develop. This is often referred to as non-communicating hydrocephalus.
It has traditionally been thought that CSF is absorbed through tiny, specialized cell clusters called arachnoid villi near the top and midline of the brain.
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