The third ventricle and fourth ventricle are connected to each other by the cerebral aqueduct also called the Aqueduct of Sylvius. CSF then flows into the subarachnoid space through the foramina of Luschka there are two of these and the foramen of Magendie only one of these.
Absorption of the CSF into the blood stream takes place in the superior sagittal sinus through structures called arachnoid villi. However, the arachnoid villi act as "one way valves" In other words, the CSF acts to cushion a blow to the head and lessen the impact. Buoyancy : because the brain is immersed in fluid, the net weight of the brain is reduced from about 1, gm to about 50 gm. 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.
Even in recent studies, it is assumed that the CSF circulation is directed towards the arachnoid villus along the ventricles and subarachnoid space [ 24 , 40 ]. VRS are a histologically defined anatomical area surrounding blood vessels as they enter the brain tissue from the subarachnoid space Initially, VRSs were believed to be connected to the subarachnoid space, allowing for free fluid transfer.
This concept was later elucidated by microscopic investigations that showed perivascular cavities as dead ends, open to the subarachnoid space but closed to the parenchyma, and therefore not a channel for flow [ 41 ].
Considering the microscopic anatomy of VRS, its thin structure is actually located on layers of endothelial, pial, and glial cells, each defined by different basal membranes [ 42 ]. The glia covering the brain parenchyma forms the outer wall of the VRSs [ 43 ].
In the capillary bed, the basal membrane of the glia merges with the outer vascular membrane, forming the VRS [ 44 ]. The arterial and venous vessels, which are located in the cortical subarachnoid space SAS , are covered by a layer of pial cells that surround the vessels. The pial sheath forms a cavity next to the vessel wall, called the perivascular space PVS [ 45 ]. At the entrance of the cortical vessels to the VRS, the pial sheaths merge with the layer of pial cells lining the brain surface, forming a funnel-like structure that accompanies the VRS to the vessels only for a short distance [ 46 ].
However, the pial sheath of the arterial vessels extends to the VRS. Near the capillary bed, the pial sheath becomes more and more windowed and leaky [ 45 ]. Studies with electron microscopy show that pial membranes separate VRS from the cortical subarachnoid space [ 46 ]. Since electron microscopy of human brain samples shows that VRS and PVS have collapsed, it has been a matter of debate whether these histologically characterized compartments are really openings or spaces [ 45 ].
However, studies in rodents have shown that VRS is filled with fluid, electron microscopic dense material [ 46 ], macrophages and other inflammatory cells [ 42 ]. Although pial cell layers separate the VRS from the cortical subarachnoid space, physiologically there is strong evidence that fluid circulates throughout the VRS.
There are species-related differences in the pial layer. In mice, for example, the pial layer is very thin, while in humans it is thicker [ 49 ]. In humans, the pial sheath is described as a sensitive but seemingly continuous layer of cells, connected by desmosomes and cavity connections but without obvious tight connections [ 50 ]. As a result of numerous experimental studies, it has been recognized that the pia mater does not have permeable properties against liquids [ 51 ] Given that the flow within the VRS depends on the pulsatility of the arteries [ 52 ], hydrostatic forces can move liquids and solutes along the pial membranes.
Although it has been shown that the pial membranes between PVS and SAS can prevent the exchange of larger molecules, the intraparenchymal injection has not been shown to spread to cisternal CSF, although it has accumulated in PVS [ 53 ].
This observation is supported by clinical findings that red blood cells are confined in the subarachnoid space and do not enter the VRS following aneurysm rupture in humans [ 49 ]. There is experimental evidence that paraarterial drainage pathways are connected to the lymphatics of the posterior skull base [ 54 ]. In reality, the solutes and fluids can be discharged through the VRS from the brain interstitium through the arteries, into the cervical lymphatics [ 55 ].
This view was supported experimentally by immunohistochemical and confocal microscopic observations showing that fluorescent dyes such as 3 kD dextran or 40 kD ovalbumin move along the basic membranes of capillaries and arteries after being injected into the corpus striatum in mice. These findings are clinically significant as beta-amyloid accumulates in the vascular wall of arterioles and arteries, based on observations in patients with cerebral amyloid angiopathy.
The size of amyloid deposition is so pronounced that it has been proposed as a natural determinant for peri-arterial drainage pathways [ 55 ]. Peri-arterial drainage of liquids and solutes has important effects not only in neurodegenerative diseases but also in immunological CNS diseases [ 55 ]. Similar to arteries, veins in the subarachnoid space have pial sheath forming a PVS [ 42 ].
Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications. Recent research challenges significant aspects of the classical model and the circulatory nature of the CSF flow has been questioned. Specific aspects now being reconsidered include the rate and site of CSF formation and absorption[ 7 — 10 ].
This review reexamines key developments that have led to the traditional concept of CSF physiology and introduces new findings that enhance our current understanding. Novel insights from molecular and cellular biology as well as neuroimaging research have shown that CSF physiology is much more complex than previously recognized. Most CSF is formed in the cerebral ventricles.
Possible sites of origin include the choroid plexus, the ependyma, and the parenchyma[ 2 ]. Anatomically, choroid plexus tissue is floating in the cerebrospinal fluid of the lateral, third, and fourth ventricles.
This tissue is well perfused by numerous villi, each having a central capillary with fenestrated endothelium. A single layer of cuboidal epithelium then covers each of these vessels. This unusual cellular anatomy forms the blood CSF barrier characterized by tight junctions at the apical end of the choroid epithelial cells rather than at the capillary endothelium within each villus[ 2 , 11 , 12 ].
Due to its glandular appearance and ventricular location, the choroid plexus has been suggested to be the major site of CSF secretion. This view was mainly based upon the historical canine experiments of Dandy.
In these experiments the foramen of Monro was occluded and a choroid plexectomy of one lateral ventricle was performed. The authors reported collapse of the ventricle without choroid plexus and dilatation of the other ventricle[ 13 ]. They concluded: "From these experiments we have the absolute proof that cerebrospinal fluid is formed from the choroid plexus.
Simultaneously it was proven that the ependyma lining the ventricles is not concerned in the production of cerebrospinal fluid"[ 14 ]. Interestingly, the experiments of Dandy were based upon observations from only a single dog[ 1 ]. Furthermore, the experiments could not be reproduced by others[ 15 — 17 ]. From this value and the estimated arterial blood flow through the choroid plexus, a CSF secretion rate was calculated that came very close to the estimated rate of total CSF absorption[ 18 ].
Second, these findings were substantiated by concordance with experiments in which the CSF production rate was assessed in the isolated and extracorporally-perfused choroid plexus[ 19 — 22 ]. These experiments, however, were criticized because of inherent large errors possible in the experimental technique since the various preparations all required considerable operative manipulations[ 1 , 2 , 11 ].
Furthermore, other experimental studies, including those with radioactive water provided evidence that at least some CSF must come from a source other than the choroid plexus, presumably the brain tissue itself[ 23 — 25 ]. An even higher rate of ependymal fluid secretion was derived from experiments investigating spinal cord ependyma[ 27 ]. Again, these experiments were criticized because of the "drastic experimental procedures" used.
It was concluded that "it may be wise to reserve final judgment on this question"[ 11 ]. The capillary-astrocyte complex of the blood—brain barrier BBB has been implicated as an active producer of brain interstitial fluid ISF. The ISF secreted at the blood—brain barrier is coupled with shifts of extracellular fluid between brain and CSF, eventually leading to the net formation of CSF[ 28 , 29 ].
The rate of ISF formation was estimated from the clearance rate of tracer substances, which were injected into the brain parenchyma. It was assumed that the rate of clearance provides an estimate of the rate of ISF secretion at the blood—brain barrier. Accordingly, even a recent review concluded that "the working hypothesis that the BBB is a fluid generator, although attractive, needs substantiation"[ 4 ].
Historically, the absorption of CSF into the circulating blood is most notable across the arachnoid villi[ 3 , 31 , 32 ]. It was stated: "From a purely anatomical point of view, these arachnoid villi are obvious regions for the drainage of CSF into the vascular system…" page in[ 33 ]. The notion of the arachnoid villi being the major site of CSF absorption is actually based on the early experiments of Key and Retzius who injected colored gelatin into the CSF space of human cadavers.
They reported the distribution of the dye throughout the entire CSF system and its passage across the arachnoid villi into the venous sinuses[ 34 ]. However, their results were questioned since the dye was injected at a pressure of up to 60 mmHg. It was suggested that the high pressure during the dye injection could cause rupture of the arachnoid villi and absorption into the sinuses[ 35 ]. Therefore, Weed performed dye injection experiments at pressures of only 9—13 mmHg that also attempted to determine whether or not the injected dye particles themselves could obstruct the normal drainage pathways.
Isotonic solutions of non-toxic dyes ammonium citrate and potassium ferrocyanide were infused that precipitated granules of Prussian blue before the animals were intravitally fixed with acidified formalin. Weed reported the distribution of the dye particles throughout the entire CSF space, filling the arachnoid villi along the sagittal sinus, eventually invading the dural wall of the sinus.
Notably, only some granular material was found in the lumen of the sinus[ 35 , 36 ]. The authors also stated as another important result: "No evidence has been afforded in our observations of the escape of cerebrospinal fluid into cerebral veins or capillaries"[ 37 ]. Weed performed numerous pilot experiments in his effort to identify a dye solution that was best suited for his studies: "Many solutions were tried, but all proved unsatisfactory because of their toxicity or their diffuse tissue staining"[ 36 ].
One could argue, therefore, that Weed inadvertently excluded those solutions in which the absorption of CSF throughout the entire brain parenchyma would have been the result. Electron microscopy studies performed on arachnoid villi revealed a pressure-sensitive vacuolation cycle of pores, which act as one-way valves and allow for the transcellular bulk transport of fluid[ 38 , 39 ].
Extracorporal perfusion of excised dura demonstrated the passage of particles up to the size of erythrocytes[ 40 ]. Considerable portions of CSF may be absorbed into the cervical lymphatics[ 2 ]. The perineural subarachnoid space of cranial nerves, which is connected to the cranial CSF space, was suggested as a pathway for the drainage of CSF into the lymphatics of the extracranial soft tissue at the skull base[ 2 ].
Though it is obvious that CSF drains into the lymphatics, the physiological significance of this CSF absorption route is still a matter of debate. This finding led to the conclusion that only a small fraction of CSF drains via the lymphatic channels. Interestingly much RISA was drained via the cerebral perivascular spaces as well as by the passage from the subarachnoid space of olfactory lobes into the submucosal spaces of the nose and thus to the lymphatics [ 43 ].
Intravital microscopy of the exposed cervical lymph nodes during the cisternal infusion of ink revealed that particle movement was dependent on the respiratory cycle: during inspiration the speed of particle movement was 10—20 mm s -1 , while no movement was observed during the expiration phase[ 44 ].
It is important to note that the CSF and ISF spaces communicate with the cervical lymphatics via two anatomically different routes, i. Extracranial organs feature fluid exchange across the capillary bed that is driven by hydrodynamic and osmotic pressure gradients.
However, absorption of CSF into cerebral capillaries has been disputed because it was thought that the absorption of CSF is not dependent on osmotic forces. This notion was based on experiments in which dextran solutions of different osmolality were infused into the ventricles of cats at a constant pressure of 27 mmHg. The measured infusion rate, which should equal the CSF absorption rate, decreased by the same extent. The decrease of the absorption rate was explained by the increased CSF viscosity[ 33 ].
Interestingly, a more recent animal study failed to reproduce these earlier experiments, since it was shown that 3 H 2 O from the bloodstream enters osmotically loaded cerebrospinal fluid significantly faster[ 46 ]. Since, historically, osmolality was assumed to not be relevant for CSF absorption, hydrodynamic pressure gradients would be the only driving forces for CSF drainage into the brain capillaries and post-capillary venules.
It was also assumed that any absorption would require a CSF pressure higher than the intravascular pressure and that this would cause the collapse of the vessels and prevent absorption of CSF[ 2 , 47 ]. These statements from the s and s were actually defining the understanding of CSF physiology for decades until BBB and aquaporin AQP studies clearly indicated the involvement of osmotic forces in brain water homeostasis for discussion see below.
In , Masserman calculated the rate of CSF formation in patients by measuring the time needed for the CSF pressure to return to its initial level following drainage of a standard volume of CSF by lumbar puncture[ 48 ]. After drainage of 20 to 35 mL of CSF, pressure was restored at a rate of about 0.
The validity of results obtained in this way was criticized because the Masserman technique assumes that neither formation nor absorption rates are changed by alterations in pressure.
However, the absorption of CSF varies greatly with changes in intracranial pressure[ 49 , 50 ]. Modifications of the Masserman technique applied sophisticated infusion and drainage protocols, which recorded and controlled the CSF pressure during the measurement period see for example[ 51 ]. Despite numerous research efforts, more sophisticated experimental protocols did not yield CSF formation rates that differed from earlier work.
The ventriculo-cisternal perfusion "Pappenheimer" technique represents a more quantitative approach for the assessment of CSF formation rate.
Inulin or other macromolecules, which pass through the ventricular space without being absorbed, are infused at a constant rate into the cerebral ventricles.
CSF formation is calculated from the measurement of the extraventricular cisternal or spinal CSF concentration of inulin. It is assumed that any dilution of inulin between the inflow cannula and outflow cannula results from the admixture of freshly formed CSF.
In addition, the test procedure allows for the calculation of the CSF absorption rate from the clearance of inulin at the extraventricular site in animals the cisterna magna, in man the lumbar space [ 49 ].
An important disadvantage was that the procedure was difficult to apply in clinical settings because of its invasiveness: The hour long infusion required both a ventricular and extraventricular CSF catheter.
Also, both infusion rate and infused volume exceeded the physiological range of CSF flow by far. Despite these obstacles, clinical measurements were performed in brain tumor patients who received ventricular catheters for chemotherapy purposes: In patients 9—61 years old the average flow rate was 0.
These results were confirmed in children with brain tumors[ 53 ]. Furthermore, similar data are available from hydrocephalus patients[ 54 ]. Though more precise, the ventriculocisternal or ventriculolumbar perfusion techniques yielded results remarkably close to those assessed by the Masserman technique[ 2 ].
Findings from both the Masserman and the Pappenheimer techniques were supported by neuroradiological investigations applying serial CT scans to assess the ventricular washout of metrizamide, a water soluble contrast media.
The rate of right lateral ventricular CSF formation ranged from 0. Hence, the assessment of the CSF formation and absorption rates remains a matter of debate even today. It has been suggested that a method that is less invasive than the Pappenheimer method ventriculo-cisternal perfusion and more reliable than the Masserman method is sorely needed[ 50 ].
The concept of the "third circulation" suggesting that CSF flows through the ventricles, cisterns and subarachnoid space SAS and is reabsorbed into the blood at the arachnoid villi, was introduced by Cushing in [ 57 , 58 ].
This notion was a radical departure from the contemporary view that the CSF moved by ebb and flow[ 1 ]. Since Cushing, the circulatory, bulk flow character of the CSF system has remained unquestioned by the majority of researchers. Even recent reviews assume a directed CSF circulation through the ventricles and the subarachnoid space toward the arachnoid villi[ 1 , 5 , 32 ].
Nevertheless, as will be discussed below, this understanding of CSF circulation appears to be a rough simplification of a much more complicated situation. Anatomically the VRS refers to a histologically-defined space, which surrounds blood vessels arterioles and venules when penetrating from the subarachnoid space into the brain tissue.
Originally, it was thought that the VRS is connected to the subarachnoid space, allowing for a free fluid communication. It was suggested that interstitial fluid may be outwardly drained along these pathways into the SAS and eventually towards the arachnoid villi[ 35 ]. Later this concept was questioned on the basis of light microscopic examinations, which depicted perivascular spaces as cul-de-sacs, open to the subarachnoid space but closed towards the parenchyma and therefore not a channel for flow[ 59 ].
The first systematic electron microscopic study of blood vessels entering the cerebral cortex confirmed this view. In addition it was reported that small arterioles entering the cortex carry with them to the point at which they become capillaries an extension of the subarachnoid space[ 60 ]. Actually, these findings, showing the obliteration of the VRS at the capillary bed, led to the rejection of the earlier theories on the existence of a perivascular CSF circulation.
As discussed by others[ 61 ], these morphological findings eventually supported the general belief that the interstitial fluid ISF is stagnant in the central nervous system. Morphology of Virchow Robin and perivascular spaces. Delineated by basal membranes of glia, pia and endothelium, the Virchow Robin space VRS depicts the space surrounding vessels penetrating into the parenchyma.
The VRS is obliterated at the capillaries where the basement membranes of glia and endothelium join. The complex pial architecture may be understood as an invagination of both cortical and vessel pia into the VRS. The pial funnel is not a regular finding. The pial sheath around arteries extends into the VRS, but becomes more fenestrated and eventually disappears at the precapillary section of the vessel.
Unlike arteries as shown in this figure , veins do not possess a pial sheath inside the VRS. ISF may drain by way of an intramural pathway along the basement membranes of capillaries and arterioles into the lymphatics at the base of the skull green arrows.
It should be noted that the figure does not depict the recently suggested periarterial flow from the SAS into the parenchyma and an outward flow into the cervical lymphatics along the veins for discussion see text "Current research".
Also, it is still a matter of debate whether the Virchow Robin space, extending between the outer basement membrane of the vessel and the glia, represents a fluid-filled open space see text. The current understanding of the microscopic anatomy of the VRS is more complex Figure 1. Actually, its fine structure is built upon endothelial, pial, and glial cell layers, each of them delineated by distinct basement membranes[ 62 — 64 ]. The glial membrane glia limitans covering the brain parenchyma forms the outer wall of the VRS[ 65 ].
At the capillary bed, the basement membrane of the glia fuses with the outer vascular membrane thereby occluding the Virchow-Robin space[ 66 , 67 ]. Arterial and venous vessels running within the cortical subarachnoid space are covered with a pial cell layer, which ensheaths the vessels.
The pial sheath creates a space next to the vessel wall, which is referred to as perivascular space PVS [ 68 ]. At the site of the entrance of the cortical vessels into the VRS, their pial sheath joins with the pial cell layer covering the brain surface forming a funnel like structure, which accompanies the vessels into the VRS though for a short distance only[ 69 , 70 ].
However, the pial sheath of the arterial, but not venous, vessels extends into the VRS. Near the capillary bed, the pial sheath becomes more and more fenestrated and leaky[ 68 ]. It is important to note that the nomenclature is not used consistently. Some authors use the terms "Virchow Robin space" and "perivascular space" as synonyms[ 71 ], while others use the terms to name different spaces as discussed above[ 72 ].
Ultrastructural electron microscopic studies agree that pial membranes separate the VRS from the cortical subarachnoid space[ 65 , 68 , 70 ]. Since electron microscopy of human brain specimens shows that the VRS and the PVS are collapsed[ 68 ], it is a matter of debate whether these histologically-characterized compartments are actually open or just potential spaces.
However, studies in rodents have demonstrated the VRS filled with fluid, electron microscopic dense material[ 70 ], macrophages and other blood born inflammatory cells[ 64 , 67 ]. Possibly, different fixation procedures may explain this discrepancy: rodent brains undergo intra-vital perfusion fixation, while the studies in man have to rely on specimens, which are fixed extra-corporally. Although pial cell layers obviously separate the VRS from the cortical subarachnoid space, physiologically there is strong evidence indicating that fluid circulates along the VRS Figure 2.
Following the injection of horseradish peroxidase HRP into the lateral ventricles or subarachnoid space of anesthetized cats and dogs, light microscopic examination of serial brain sections has been performed utilizing a sensitive histochemical technique tetramethylbenzidine incubation [ 73 ].
The authors reported the distribution of tracer reaction product within the VRS and along the basal laminae around capillaries. The influx into these spaces was very rapid since the intraparenchymal microvasculature was clearly outlined 6 min after the infusion of HRP. Electron microscopy of sections incubated after 10 or 20 min of HRP circulation confirmed the paravascular location of the reaction product, which was also dispersed throughout the extracellular spaces ECS of the adjacent parenchyma.
The rapid paravascular influx of HRP could be prevented by halting or diminishing the pulsations of the cerebral arteries by aortic occlusion or by partial ligation of the brachiocephalic artery. However, it should be noted that others were not able to reproduce these findings; Krisch et al.
Also, another study reported that following microinjection into the VRS or the subarachnoid space of rats, tracers e. India ink, albumin labeled with colloidal gold, Evans blue, rhodamine remained largely in the VRS, the cortical subpial space and the core of subarachnoid trabeculae. Nevertheless, bulk flow of fluid within the VRS, around both arteries and veins, was suggested from video-densitometric measurements of fluorescently labeled albumin.
However, the observed flow was slow and its direction varied in an unpredictable way[ 71 ]. Furthermore, it was shown that, following intracerebral injection, India ink particles concentrated in the VRS, but were then rapidly ingested by perivascular cells. Notably, very little movement of carbon-labeled perivascular cells and perivascular macrophages was seen after 2 years[ 74 ]. Diagram representing fluid movements at the Virchow Robin space.
Glial blue lines and pial yellow lines cell membranes enclose the VRS and control fluid exchange. Note, that it is a matter of debate whether the VRS represents an open fluid fill space see text for discussion.
Both experimental and clinical evidence indicate the existence of a pathway along the basement membranes of capillaries, arterioles, and arteries for the drainage of ISF and solutes into the lymphatic system red lines and green arrows.
It is unclear, whether the subpial perivascular spaces around arteries and veins light blue serve as additional drainage pathways. Also, the proposed glymphatic pathway connecting the arterial and venous VRS with the venous perivascular space black arrows is still a matter of debate. Since there is obviously at least some circulation of CSF into and out of the VRS, it raises the question how fluid and tracers could cross the pial membranes separating the VRS from the subarachnoid space.
Ultrastructure studies have depicted the pial barrier as a delicate, sometimes single-cell layered structure[ 75 ]. There are considerable species differences: in the mouse the pial layer was found to be extremely thin, while in man its structure was significantly thicker[ 76 ]. Notably, in man the pial barrier was still described as a delicate yet apparently continuous layer of cells, which were joined by desmosomes and gap junctions but had no obvious tight junctions[ 77 ].
According to such morphological studies, it was recognized that the pia is not impermeable to fluids[ 61 ]. Since, in a similar fashion, the ependymal cell layers covering the inner ventricular surfaces of the brain are not connected by tight junctions[ 78 ], it was suggested that "CSF communicates with the ISF across the inner ependymal and outer pial surfaces of the brain"[ 61 ].
If one assumes that the flow within the VRS depends on the pulsatility of the arteries[ 73 , 79 ], hydrostatic forces may drive fluids and solutes across the pial membranes. However, while the VRS basically allows for the bi-directional exchange between CSF and ISF, no quantitative data are available that describe the extent and kinetics of such fluid movements.
Although it has been shown that pial membranes between the PVS and the SAS could prevent the exchange of larger molecules, since tracer, following intraparenchymal injection, accumulated within the PVS but was not distributed into the cisternal CSF[ 80 ]. This observation is supported by clinical findings that following aneurysmal rupture in man, red blood cells are confined to the subarachnoid space, and do not enter the VRS[ 76 ].
It has also been shown both experimentally and clinically that the PVS and possibly more importantly intramural pathways between the basement membranes of the wall of arterioles and arteries provide drainage for the ISF and waste molecules of the brain.
There is experimental evidence that the para-arterial drainage pathways are connected to the lymphatics of the exterior skull base[ 81 , 82 ]. Actually, solutes and fluid may be drained along the arteries from the brain interstitium via the VRS into the cervical lymphatics[ 81 , 83 ], reviewed by Weller[ 45 ]. Supporting this notion are the immunohistochemical and confocal microscopic observations that soluble fluorescent tracers 3 kD dextran or 40 kD ovalbumin move from the brain parenchyma along the basement membranes of capillaries and arteries following its injection of into the corpus striatum of mice.
This pathway may not serve for the transport of particles or cells, since fluospheres diameter 0. Clearance of solutes along this pathway could be prevented by cardiac arrest[ 83 ]. These findings are clinically significant since based upon observations in patients with cerebral amyloid angiopathy, beta-amyloid is deposited in the vascular wall of arterioles and arteries.
Interestingly, the extent of amyloid deposition is so prominent that it was suggested as a natural tracer for the peri-arterial drainage pathways[ 83 ]. The peri-arterial drainage of fluids and solutes has important implications not only in neurodegenerative diseases, but in addition in immunological CNS diseases, see for comprehensive reviews[ 45 , 85 , 86 ].
Similar to arteries, veins within the subarachnoid space possess a pial sheath forming a PVS[ 64 ]. As compared to arteries, it is less clear whether venous perivascular pathways serve as a drainage pathway for ISF and interstitial solutes. Notably, injections of tracers into the brain revealed no drainage along peri-venous channels unless there is disruption of flow in cerebral amyloid angiopathy when some tracer enter the peri-venous spaces[ 87 ].
However, recent findings[ 88 ] indicate a more significant contribution of the venous perivascular route for the drainage of ISF and solutes see discussion below. Traditionally, movement of fluids through the brain interstitial space has been attributed to diffusional processes[ 89 — 91 ], which actually are slow because of the narrowness and tortuosity of the extracellular space of the brain reviewed by[ 92 ].
Today, it is commonly accepted that "the narrow spaces between cells within the neuropil are likely to be too small to permit significant bulk flow"[ 29 ]. A recent review discusses important clinical implications regarding CNS drug delivery[ 93 ].
As commented by others[ 45 , 94 ], our current understanding includes bulk flow mechanisms for the movement and drainage of ISF along white matter tracts and the perivascular spaces. Considering the cellular architecture of pia and ependyma, it also accepted that these cellular layers represent a diffusional barrier, which actually provides a communication between ISF and CSF[ 61 ]. Experimental evidence for the existence of bulk flow mechanisms was found after microinjection of tracer into the brain.
Morphological studies revealed the VRS and the perivascular spaces as channels for fluid transport, but also revealed additional spaces between fiber tracts in white matter and the subependymal layer of the ventricle.
Analysis of the kinetics of removal of three radiolabeled tracers from brain tissue e. These three test compounds differ in their diffusion coefficient by up to a factor of five but were cleared from brain according to a single exponential rate constant.
This is consistent with removal by convection from a well-mixed compartment. For different regions of the brains of rats and rabbits, the ISF flow rate was estimated between 0. Very recently it has been shown that astrocyte water transporters, i. Interestingly, such extensive water movements were indicated by earlier radiotracer experiments.
For example in , following the intravenous injection of deuterium oxide a rapid distribution throughout all brain compartments was reported[ 99 ]. As a result, the significance of this work was not fully appreciated.
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