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How does cerebrospinal fluid circulate in the central nervous system?

How does cerebrospinal fluid circulate in the central nervous system?


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Cerebrospinal fluid (CSF) is produced in the choroid plexus of the lateral ventricles and in the 4th ventricle of the brain. CSF then circulates through the ventricles of the brain and the subarachnoid space of the meninges. CSF is returned to the venous system via the arachnoid granulations connecting the subrachnoid space with the superior sagittal sinus at the superior portion of the neurocranium.

  • What circulates the CSF such that it can return to the venous system against gravity?

  • In other words, why does CSF not all just pool in the caudal cistern?


There are several points here.

Arachnoid granulations are not the only "sinks" for CSF.

Even though it is true that most of the CSF is eliminated from ventricular system and subarachnoid space through these granulations, there are also suggestions that there are also other potential mechanism of shunting CSF into the venous system:

  1. Cranial nerves leaving CNS go through dura mater and these holes are not sealed, so it is suggested that some CSF can just go along the nerves and then accumulate in the lymphatic nodes in submucus.

  2. Dura mater is mostly perforated at the area of lamina cribrosa, that basically separates the nasal holes and our brain. Leaking through multiple small holes here CSF is accumulated into the lymphatic submucusal nodes, found in abundance here. This way is considered to be primary CSF drainage way in newborns who don't have a well developed granularities in (sub)arachnoid space.

  3. Spinal nerves, especially in the upper part of the spinal cord, also leave unsealed holes and the presence of lymphatic nodes adjacent to the places where these nerves leave the verterbral column also make them a potential place for CSF drainage.

Arachnoid granularitis do not only drain, they are capable of active CSF uptake.

CFS is not just "circulating" here going from the place of its origin in lateral ventricles to venous system. The granularities are here to actively resorb this fluid, meaning that they effectively take it up forming vacuoles and then excrete it to the venous system. Constant uptake leads to the pressure gradient (see also below!) that acts as a driving force for CSF.

Venous system has generally low pressure, thus sucking the CSF up to drainage points.

Speaking about drainage we also should consider the fact that the venous system has a pressure lower than the atmospheric pressure and much lower than pressure in any middle-sized arterial vessels. This is reached by having elastic walls and by transmitting the negative pressure from the mediastinum during the inhale, when the diaphragm and the thorax expand. This negative pressure propagates mostly to the connected vessels, including sinus system. Due to the elastic wall other parts of venous system can accommodate this negative pressure constrict their lumen, but not the sinus system which has a hard external framework formed by dura mater and bones. That is here we can measure the lowest pressure and this is the pressure that sucks CSF in into the venous system.

I hope that answers your question.


It is something of a misnomer to speak of CSF “circulation,” particularly in the spinal canal, as there is no continuous loop circulation of CSF as there is in the cardiovascular system.

For quite some time, it has been known that CSF movement results from the formation of new CSF and motion of cilia on the surface of the choroid plexus and ependyma lining the ventricles. - Fluids and Barriers of the CNS

The "circulation" of the CSF, as already mentioned, is something of a misnomer. CSF is not known to "circulate" in the manner of blood. It does get agitated by pressure differentials, and it is 'circulated' in terms of being reabsorbed and replaced every 6-7 hours. Other than that, no circulation occurs.

Blood circulation is not generated only by the heart. Pressure differentials throughout the body affect the circulation of blood as well. One that is easily demonstrated (first documented in 1733) is the effect of intrathoracic (chest) pressure on circulation. The blood pressure of healthy people falls during spontaneous inspiration. When someone takes a deep breath, the blood return to the heart via the vena cava decreases, and pressure is exerted on the right atrium. Both cause decreased filling, which will drop blood pressure. Although this is best demonstrated with a blood pressure cuff, it can be demonstrated without. An unrecommended method is exemplified in a childhood game of passing out. A Valsalva maneuver (deep breath and glottal closure) decreases blood flow to the heart. Squeezing the chest further decreases return, resulting in fainting.

The same pressure differentials agitate the CSF. Additionally, smaller movements were seen with pressure differentials caused by the beating of the heart.

By employing this respiration-induced spin labeling bSSFP cine method, we were able to visualize CSF movement induced by respiratory excursions. CSF moved cephalad (16.4 ± 7.7 mm) during deep inhalation and caudad (11.6 ± 3.0 mm) during deep exhalation in the prepontine cisternal area. Small but rapid cephalad (3.0 ± 0.4 mm) and caudad (3.0 ± 0.5 mm) movement was observed in the same region during breath holding and is thought to reflect cardiac pulsations.

This image from Wikipedia shows "circulation" that normally occurs with heartbeat.

There are other factors that cause movement of CSF, but they are intermittent and variable.

Influence of respiration on cerebrospinal fluid movement using magnetic resonance spin labeling, Yamada et. al., Fluids and Barriers of the CNS 2013, 10:36
MRI showing pulsation of CSF


Circulation of cerebrospinal fluid (CSF) through the ventricular system is driven by motile cilia on ependymal cells of the brain.

Hagenlocher C1, Walentek P, M Ller C, Thumberger T, Feistel K.Ciliogenesis and cerebrospinal fluid flow in the developing Xenopus brain are regulated by foxj1.Cilia. 2013 Sep 24;2(1):12. doi: 10.1186/2046-2530-2-12.


CSF is actively pumped in an ebb and flow manner by the pressure with our respiratory mechanism transmitted through the pelvic diaphram onto the sacral bone that pulls on the spinal dural membranes attached at S2. Think about it: the pelvic and thoracic diaphragm are linked in a respiratory phasic contraction (confirmed with MRI). The pulling on the sacral end of the dural membranes via the pelvic floor muscle will squeeze the CSF up the spinal canal into the brain with inspiration. This is a much stronger force than any ciliary or cardic induced influence of CSF flow. Recent MRI studies have confirmed this as well.


Summary

The cerebrospinal fluid (CSF) is contained in the brain ventricles and the cranial and spinal subarachnoid spaces. The mean CSF volume is 150 ml, with 25 ml in the ventricles and 125 ml in subarachnoid spaces.

CSF is predominantly, but not exclusively, secreted by the choroid plexuses. Brain interstitial fluid, ependyma and capillaries may also play a poorly defined role in CSF secretion.

CSF circulation from sites of secretion to sites of absorption largely depends on the arterial pulse wave. Additional factors such as respiratory waves, the subject's posture, jugular venous pressure and physical effort also modulate CSF flow dynamics and pressure.

Cranial and spinal arachnoid villi have been considered for a long time to be the predominant sites of CSF absorption into the venous outflow system. Experimental data suggest that cranial and spinal nerve sheaths, the cribriform plate and the adventitia of cerebral arteries constitute substantial pathways of CSF drainage into the lymphatic outflow system.

CSF is renewed about four times every 24 hours. Reduction of the CSF turnover rate during ageing leads to accumulation of catabolites in the brain and CSF that are also observed in certain neurodegenerative diseases.

The CSF space is a dynamic pressure system. CSF pressure determines intracranial pressure with physiological values ranging between 3 and 4 mmHg before the age of one year, and between 10 and 15 mmHg in adults.

Apart from its function of hydromechanical protection of the central nervous system, CSF also plays a prominent role in brain development and regulation of brain interstitial fluid homeostasis, which influences neuronal functioning.


How does cerebrospinal fluid circulate in the central nervous system? - Biology

The CNS is crucial to the operation of the body, and any compromise in the brain and spinal cord can lead to severe difficulties. The CNS has a privileged blood supply, as suggested by the blood-brain barrier. The function of the tissue in the CNS is crucial to the survival of the organism, so the contents of the blood cannot simply pass into the central nervous tissue. To protect this region from the toxins and pathogens that may be traveling through the blood stream, there is strict control over what can move out of the general systems and into the brain and spinal cord. Because of this privilege, the CNS needs specialized structures for the maintenance of circulation. This begins with a unique arrangement of blood vessels carrying fresh blood into the CNS. Beyond the supply of blood, the CNS filters that blood into cerebrospinal fluid (CSF), which is then circulated through the cavities of the brain and spinal cord called ventricles.

Blood Supply to the Brain

A lack of oxygen to the CNS can be devastating, and the cardiovascular system has specific regulatory reflexes to ensure that the blood supply is not interrupted. There are multiple routes for blood to get into the CNS, with specializations to protect that blood supply and to maximize the ability of the brain to get an uninterrupted perfusion.

Arterial Supply

The major artery carrying recently oxygenated blood away from the heart is the aorta. The very first branches off the aorta supply the heart with nutrients and oxygen. The next branches give rise to the common carotid arteries, which further branch into the internal carotid arteries. The external carotid arteries supply blood to the tissues on the surface of the cranium. The bases of the common carotids contain stretch receptors that immediately respond to the drop in blood pressure upon standing. The orthostatic reflex is a reaction to this change in body position, so that blood pressure is maintained against the increasing effect of gravity (orthostatic means “standing up”). Heart rate increases—a reflex of the sympathetic division of the autonomic nervous system—and this raises blood pressure. The internal carotid artery enters the cranium through the carotid canal in the temporal bone. A second set of vessels that supply the CNS are the vertebral arteries, which are protected as they pass through the neck region by the transverse foramina of the cervical vertebrae. The vertebral arteries enter the cranium through the foramen magnum of the occipital bone. Branches off the left and right vertebral arteries merge into the anterior spinal artery supplying the anterior aspect of the spinal cord, found along the anterior median fissure. The two vertebral arteries then merge into the basilar artery, which gives rise to branches to the brain stem and cerebellum. The left and right internal carotid arteries and branches of the basilar artery all become the circle of Willis, a confluence of arteries that can maintain perfusion of the brain even if narrowing or a blockage limits flow through one part (Figure 12.15).

Interactive Link

Watch this animation to see how blood flows to the brain and passes through the circle of Willis before being distributed through the cerebrum. The circle of Willis is a specialized arrangement of arteries that ensure constant perfusion of the cerebrum even in the event of a blockage of one of the arteries in the circle. The animation shows the normal direction of flow through the circle of Willis to the middle cerebral artery. Where would the blood come from if there were a blockage just posterior to the middle cerebral artery on the left?

Venous Return

After passing through the CNS, blood returns to the circulation through a series of dural sinuses and veins (Figure 12.16). The superior sagittal sinus runs in the groove of the longitudinal fissure, where it absorbs CSF from the meninges. The superior sagittal sinus drains to the confluence of sinuses, along with the occipital sinuses and straight sinus, to then drain into the transverse sinuses. The transverse sinuses connect to the sigmoid sinuses, which then connect to the jugular veins. From there, the blood continues toward the heart to be pumped to the lungs for reoxygenation.

Protective Coverings of the Brain and Spinal Cord

The outer surface of the CNS is covered by a series of membranes composed of connective tissue called the meninges, which protect the brain. The dura mater is a thick fibrous layer and a strong protective sheath over the entire brain and spinal cord. It is anchored to the inner surface of the cranium and vertebral cavity. The arachnoid mater is a membrane of thin fibrous tissue that forms a loose sac around the CNS. Beneath the arachnoid is a thin, filamentous mesh called the arachnoid trabeculae, which looks like a spider web, giving this layer its name. Directly adjacent to the surface of the CNS is the pia mater, a thin fibrous membrane that follows the convolutions of gyri and sulci in the cerebral cortex and fits into other grooves and indentations (Figure 12.17).

Dura Mater

Like a thick cap covering the brain, the dura mater is a tough outer covering. The name comes from the Latin for “tough mother” to represent its physically protective role. It encloses the entire CNS and the major blood vessels that enter the cranium and vertebral cavity. It is directly attached to the inner surface of the bones of the cranium and to the very end of the vertebral cavity. There are infoldings of the dura that fit into large crevasses of the brain. Two infoldings go through the midline separations of the cerebrum and cerebellum one forms a shelf-like tent between the occipital lobes of the cerebrum and the cerebellum, and the other surrounds the pituitary gland. The dura also surrounds and supports the venous sinuses.

Arachnoid Mater

The middle layer of the meninges is the arachnoid, named for the spider-web–like trabeculae between it and the pia mater. The arachnoid defines a sac-like enclosure around the CNS. The trabeculae are found in the subarachnoid space , which is filled with circulating CSF. The arachnoid emerges into the dural sinuses as the arachnoid granulations , where the CSF is filtered back into the blood for drainage from the nervous system. The subarachnoid space is filled with circulating CSF, which also provides a liquid cushion to the brain and spinal cord. Similar to clinical blood work, a sample of CSF can be withdrawn to find chemical evidence of neuropathology or metabolic traces of the biochemical functions of nervous tissue.

Pia Mater

The outer surface of the CNS is covered in the thin fibrous membrane of the pia mater. It is thought to have a continuous layer of cells providing a fluid-impermeable membrane. The name pia mater comes from the Latin for “tender mother,” suggesting the thin membrane is a gentle covering for the brain. The pia extends into every convolution of the CNS, lining the inside of the sulci in the cerebral and cerebellar cortices. At the end of the spinal cord, a thin filament extends from the inferior end of CNS at the upper lumbar region of the vertebral column to the sacral end of the vertebral column. Because the spinal cord does not extend through the lower lumbar region of the vertebral column, a needle can be inserted through the dura and arachnoid layers to withdraw CSF. This procedure is called a lumbar puncture and avoids the risk of damaging the central tissue of the spinal cord. Blood vessels that are nourishing the central nervous tissue are between the pia mater and the nervous tissue.

Disorders of the Meninges

Meningitis is an inflammation of the meninges, the three layers of fibrous membrane that surround the CNS. Meningitis can be caused by infection by bacteria or viruses. The particular pathogens are not special to meningitis it is just an inflammation of that specific set of tissues from what might be a broader infection. Bacterial meningitis can be caused by Streptococcus, Staphylococcus, or the tuberculosis pathogen, among many others. Viral meningitis is usually the result of common enteroviruses (such as those that cause intestinal disorders), but may be the result of the herpes virus or West Nile virus. Bacterial meningitis tends to be more severe. The symptoms associated with meningitis can be fever, chills, nausea, vomiting, light sensitivity, soreness of the neck, or severe headache. More important are the neurological symptoms, such as changes in mental state (confusion, memory deficits, and other dementia-type symptoms). A serious risk of meningitis can be damage to peripheral structures because of the nerves that pass through the meninges. Hearing loss is a common result of meningitis. The primary test for meningitis is a lumbar puncture. A needle inserted into the lumbar region of the spinal column through the dura mater and arachnoid membrane into the subarachnoid space can be used to withdraw the fluid for chemical testing. Fatality occurs in 5 to 40 percent of children and 20 to 50 percent of adults with bacterial meningitis. Treatment of bacterial meningitis is through antibiotics, but viral meningitis cannot be treated with antibiotics because viruses do not respond to that type of drug. Fortunately, the viral forms are milder.

Interactive Link

Watch this video that describes the procedure known as the lumbar puncture, a medical procedure used to sample the CSF. Because of the anatomy of the CNS, it is a relative safe location to insert a needle. Why is the lumbar puncture performed in the lower lumbar area of the vertebral column?

The Ventricular System

Cerebrospinal fluid (CSF) circulates throughout and around the CNS. In other tissues, water and small molecules are filtered through capillaries as the major contributor to the interstitial fluid. In the brain, CSF is produced in special structures to perfuse through the nervous tissue of the CNS and is continuous with the interstitial fluid. Specifically, CSF circulates to remove metabolic wastes from the interstitial fluids of nervous tissues and return them to the blood stream. The ventricles are the open spaces within the brain where CSF circulates. In some of these spaces, CSF is produced by filtering of the blood that is performed by a specialized membrane known as a choroid plexus. The CSF circulates through all of the ventricles to eventually emerge into the subarachnoid space where it will be reabsorbed into the blood.

The Ventricles

There are four ventricles within the brain, all of which developed from the original hollow space within the neural tube, the central canal. The first two are named the lateral ventricles and are deep within the cerebrum. These ventricles are connected to the third ventricle by two openings called the interventricular foramina. The third ventricle is the space between the left and right sides of the diencephalon, which opens into the cerebral aqueduct that passes through the midbrain. The aqueduct opens into the fourth ventricle, which is the space between the cerebellum and the pons and upper medulla (Figure 12.18).

As the telencephalon enlarges and grows into the cranial cavity, it is limited by the space within the skull. The telencephalon is the most anterior region of what was the neural tube, but cannot grow past the limit of the frontal bone of the skull. Because the cerebrum fits into this space, it takes on a C-shaped formation, through the frontal, parietal, occipital, and finally temporal regions. The space within the telencephalon is stretched into this same C-shape. The two ventricles are in the left and right sides, and were at one time referred to as the first and second ventricles. The interventricular foramina connect the frontal region of the lateral ventricles with the third ventricle. The third ventricle is the space bounded by the medial walls of the hypothalamus and thalamus. The two thalami touch in the center in most brains as the massa intermedia, which is surrounded by the third ventricle. The cerebral aqueduct opens just inferior to the epithalamus and passes through the midbrain. The tectum and tegmentum of the midbrain are the roof and floor of the cerebral aqueduct, respectively. The aqueduct opens up into the fourth ventricle. The floor of the fourth ventricle is the dorsal surface of the pons and upper medulla (that gray matter making a continuation of the tegmentum of the midbrain). The fourth ventricle then narrows into the central canal of the spinal cord. The ventricular system opens up to the subarachnoid space from the fourth ventricle. The single median aperture and the pair of lateral apertures connect to the subarachnoid space so that CSF can flow through the ventricles and around the outside of the CNS. Cerebrospinal fluid is produced within the ventricles by a type of specialized membrane called a choroid plexus . Ependymal cells (one of the types of glial cells described in the introduction to the nervous system) surround blood capillaries and filter the blood to make CSF. The fluid is a clear solution with a limited amount of the constituents of blood. It is essentially water, small molecules, and electrolytes. Oxygen and carbon dioxide are dissolved into the CSF, as they are in blood, and can diffuse between the fluid and the nervous tissue.

Cerebrospinal Fluid Circulation

The choroid plexuses are found in all four ventricles. Observed in dissection, they appear as soft, fuzzy structures that may still be pink, depending on how well the circulatory system is cleared in preparation of the tissue. The CSF is produced from components extracted from the blood, so its flow out of the ventricles is tied to the pulse of cardiovascular circulation. From the lateral ventricles, the CSF flows into the third ventricle, where more CSF is produced, and then through the cerebral aqueduct into the fourth ventricle where even more CSF is produced. A very small amount of CSF is filtered at any one of the plexuses, for a total of about 500 milliliters daily, but it is continuously made and pulses through the ventricular system, keeping the fluid moving. From the fourth ventricle, CSF can continue down the central canal of the spinal cord, but this is essentially a cul-de-sac, so more of the fluid leaves the ventricular system and moves into the subarachnoid space through the median and lateral apertures. Within the subarachnoid space, the CSF flows around all of the CNS, providing two important functions. As with elsewhere in its circulation, the CSF picks up metabolic wastes from the nervous tissue and moves it out of the CNS. It also acts as a liquid cushion for the brain and spinal cord. By surrounding the entire system in the subarachnoid space, it provides a thin buffer around the organs within the strong, protective dura mater. The arachnoid granulations are outpocketings of the arachnoid membrane into the dural sinuses so that CSF can be reabsorbed into the blood, along with the metabolic wastes. From the dural sinuses, blood drains out of the head and neck through the jugular veins, along with the rest of the circulation for blood, to be reoxygenated by the lungs and wastes to be filtered out by the kidneys (Table 12.2).

Interactive Link

Watch this animation that shows the flow of CSF through the brain and spinal cord, and how it originates from the ventricles and then spreads into the space within the meninges, where the fluids then move into the venous sinuses to return to the cardiovascular circulation. What are the structures that produce CSF and where are they found? How are the structures indicated in this animation?

Table 12.2.
Components of CSF Circulation
Lateral ventricles Third ventricle Cerebral aqueduct Fourth ventricle Central canal Subarachnoid space
Location in CNS Cerebrum Diencephalon Midbrain Between pons/upper medulla and cerebellum Spinal cord External to entire CNS
Blood vessel structure Choroid plexus Choroid plexus None Choroid plexus None Arachnoid granulations

Blood Brain Barrier

The choriod plexus is the network of blood vessels and ependymal cells on surface of the ventricles. The ependymal cells of this choroid plexus secrete the CSF. Overall the close proximity of ependymal cells and blood vessels create a blood-brain barrier (BBB). The brain requires large amounts of oxygen and glucose but other items in blood may harm it, hence the barrier. At the capillaries there is a BBB of tight endothelial cells and basement membrane at the choriod plexus the blood-CSF barrier due to tight junctions between ependymal cells

Disorders of the Central Nervous System

The supply of blood to the brain is crucial to its ability to perform many functions. Without a steady supply of oxygen, and to a lesser extent glucose, the nervous tissue in the brain cannot keep up its extensive electrical activity. These nutrients get into the brain through the blood, and if blood flow is interrupted, neurological function is compromised. The common name for a disruption of blood supply to the brain is a stroke. It is caused by a blockage to an artery in the brain. The blockage is from some type of embolus: a blood clot, a fat embolus, or an air bubble. When the blood cannot travel through the artery, the surrounding tissue that is deprived starves and dies. Strokes will often result in the loss of very specific functions. A stroke in the lateral medulla, for example, can cause a loss in the ability to swallow. Sometimes, seemingly unrelated functions will be lost because they are dependent on structures in the same region. Along with the swallowing in the previous example, a stroke in that region could affect sensory functions from the face or extremities because important white matter pathways also pass through the lateral medulla. Loss of blood flow to specific regions of the cortex can lead to the loss of specific higher functions, from the ability to recognize faces to the ability to move a particular region of the body. Severe or limited memory loss can be the result of a temporal lobe stroke. Related to strokes are transient ischemic attacks (TIAs), which can also be called “mini-strokes.” These are events in which a physical blockage may be temporary, cutting off the blood supply and oxygen to a region, but not to the extent that it causes cell death in that region. While the neurons in that area are recovering from the event, neurological function may be lost. Function can return if the area is able to recover from the event. Recovery from a stroke (or TIA) is strongly dependent on the speed of treatment. Often, the person who is present and notices something is wrong must then make a decision. The mnemonic FAST helps people remember what to look for when someone is dealing with sudden losses of neurological function. If someone complains of feeling “funny,” check these things quickly: Look at the person’s face. Does he or she have problems moving Face muscles and making regular facial expressions? Ask the person to raise his or her Arms above the head. Can the person lift one arm but not the other? Has the person’s Speech changed? Is he or she slurring words or having trouble saying things? If any of these things have happened, then it is Time to call for help. Sometimes, treatment with blood-thinning drugs can alleviate the problem, and recovery is possible. If the tissue is damaged, the amazing thing about the nervous system is that it is adaptable. With physical, occupational, and speech therapy, victims of strokes can recover, or more accurately relearn, functions.


CSF Production

Between 50 to 70% of CSF is produced in the brain by modified ependymal cells in the choroid plexus, and the remainder is formed around blood vessels and along ventricular walls. It circulates from the lateral ventricles to the foramen of Monro (interventricular foramen), third ventricle, aqueduct of Sylvius (cerebral aqueduct), fourth ventricle, foramen of Magendie (median aperture), foramen of Luschka (lateral apertures), and the subarachnoid space over the brain and the spinal cord. CSF is reabsorbed into venous sinus blood via arachnoid granulations.

Subarachnoid Cavity: Diagrammatic representation of a section across the top of the skull, showing the membranes of the brain with the subarachnoid cavity visible on the left.

The Choroid Plexus: This diagram indicates the (1) posterior medullary velum (2) choroid plexus (3) cisterna cerebellomedullaris of subarachnoid cavity (4) central canal (5) corpora quadrigemina (6) cerebral peduncle (7) anterior medullary velum (8) ependymal lining of ventricle (9) cisterna pontis of subarachnoid cavity

CSF is produced at a rate of 500 ml/day. Since the subarachnoid space around the brain and spinal cord can contain only 135 to 150 ml, large amounts are drained into the blood through arachnoid granulations in the superior sagittal sinus. Thus, the CSF turns over about 3.7 times a day. This continuous flow into the venous system dilutes the concentration of larger, lipid-insoluble molecules penetrating the brain and CSF. The CSF contains approximately 0.3% plasma proteins, or approximately 15 to 40 mg/dL, depending on the sampling site.


Flow of CSF

CSF Production

The CSF is produced by the choroid plexus which can be found in the two lateral ventricles, and in the roof of the third and fourth ventricles. Around 500 ml is produced each day, with around 150-250 ml being present in the body at any one time.

The choroid plexus is composed of a fenestrated endothelium, a pial layer and a layer of specialised ependymal cells. The blood plasma is filtered through the fenestrated endothelial layer, only allowing passage for certain substances. This is followed by active transport of substances through the ependymal cells. Some substances get transferred by passive transport and diffusion of water. This allows osmolarity to be maintained.

CSF is produced continuously which keeps the fluid in circulation around the central nervous system. The fluid will move from the lateral ventricle to the third and then to the fourth ventricle. From the fourth ventricle, the fluid moves out into the subarachnoid space and/or the central canal of the spinal cord through the two lateral foramina of Luschka and the medial foramen of Magendie.

CSF Clearance

CSF gets drained into the superior sagittal venous sinus through the arachnoid villi. The pressure gradient between the subarachnoid space and the venous sinus results in the fluid moving through the arachnoid villi.

Further information on the anatomy of the ventricles and drainage of CSF can be found here.

[caption align="aligncenter"] Fig 1.0 - Overview of the cerebrospinal fluid distribution in the CNS.[/caption]

Where does the cerebrospinal fluid circulate?

CSF is produced mainly by a structure called the choroid plexus in the lateral, third and fourth ventricles. CSF flows from the lateral ventricle to the third ventricle through the interventricular foramen (also called the foramen of Monro).

Similarly, where does the cerebrospinal fluid CSF circulate quizlet? Terms in this set (3) 1)The choroid plexus of each ventricle produces CSF. 2)CSF flows through the ventricles and into the subarachnoid space via the median and lateral apertures. 3)CSF flows through the subarachnoid space.

Additionally, how does CSF circulate?

Cerebrospinal Fluid Circulation and Absorption Beginning in the lateral ventricles, CSF flows through two passageways into the third ventricle. CSF is absorbed through blood vessels over the surface of the brain back into the bloodstream. Some absorption also occurs through the lymphatic system.

According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi.


Mechanism

CSF is continuously secreted with an unchanging composition, functioning to maintain a stable environment within the brain.[3] CSF is propelled along the neuroaxis from the site of secretion to the site of absorption, mainly by the rhythmic systolic pulse wave within the choroidal arteries. Lesser determinants of CSF flow are frequency of respiration, posture, venous pressure of the jugular vein, the physical effort of the subject, and time of day.[2]

CSF is secreted by the CPs located within the ventricles of the brain, with the two lateral ventricles being the primary producers. CSF flows throughout the ventricular system unidirectionally in a rostral to caudal manner. CSF produced in the lateral ventricles would travel through the interventricular foramina to the third ventricle, through the cerebral aqueduct to the fourth ventricle, and then through the median aperture (also known as the foramen of Magendie) into the subarachnoid space at the base of the brain. Once in the subarachnoid space, the CSF begins to have a gentle multidirectional flow that creates an equalization of composition throughout the CSF. The CSF flows over the surface of the brain and down the length of the spinal cord while in the subarachnoid space. It leaves the subarachnoid space through arachnoid villi found along the superior sagittal venous sinus, intracranial venous sinuses, and around the roots of spinal nerves.

Arachnoid villi are protrusions of arachnoid mater through the dura mater into the lumen of a venous sinus. A 3 to 5 mmHg pressure gradient between the subarachnoid space and venous sinus pulls CSF into the venous outflow system through the arachnoid villi that help in its absorption.਌SF may also enter into the lymphatic system via the nasal cribriform plate or spinal nerve roots. The clearance of CSF is dependent upon the posture of the subject, pressure differentials, and pathophysiology.[1][2]


Review

Traditional understanding of CSF physiology

CSF formation

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].

There were two other sets of experiments that were thought to be "crucial" in support of Dandy’s thesis [1]: First, the hematocrit of the choroid plexus blood was found to be 1.15 times greater than of that of the systemic arterial blood. 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]. From perfusion studies performed on isolated regions of the ependymal surface it was calculated that nearly 30% of the total CSF production may come from the ependyma [26]. 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𠄻rain barrier (BBB) has been implicated as an active producer of brain interstitial fluid (ISF). The ISF secreted at the blood𠄻rain 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𠄻rain barrier. The calculated rate of formation was substantially lower (1/100 when normalized for barrier surface area) than the choroid plexus production rate [30]. Accordingly, even a recent review concluded that "the working hypothesis that the BBB is a fluid generator, although attractive, needs substantiation" [4].

CSF absorption

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 486 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� 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’s findings formed the basis for the principal understanding of CSF absorption, accepted by the majority of researchers today. 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. Five hours after the injection of albumin dye into the CSF space of rabbits only 5% is typically seen draining into the cervical lymph nodes [41]. This finding led to the conclusion that only a small fraction of CSF drains via the lymphatic channels. However, in the same period of time only 14% of the injected dye was found in the blood, revealing that lymphatic channels contributed to 26% of the tagged protein that had left the central nervous system and entered the blood stream [2]. Following the infusion of iodine-labeled serum human albumin into sheep, it was determined that 40�% of total volume of CSF is absorbed from the cranial compartment by extracranial lymphatics [42]. A lymphatic drainage fraction of 50% was estimated from the injection of radioiodinated albumin (RISA) into the brain of rabbits. 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� 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.e. the perineural subarachnoid space of cranial nerves and a "prelymphatic" pathway along the arterioles and arteries of the brain (see discussion below, reviewed by [45]).

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 H2O 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 1970s and 1980s 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).

Assessment of CSF formation and absorption rate

In 1931, 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 0.32 ml min -1 . 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� years old) the average flow rate was 0.37 ml min -1 , the maximum absorption capacity was 1.3 ml.min -1 [52]. 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 0.0622 to 0.103 ml min -1 [55,56]. 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].

CSF circulation

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 1926 [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. This especially holds true for the circulation of CSF along the Virchow–Robin spaces (VRS). The current classical view assumes that CSF flow along the VRS is slow and physiologically not important [4,5].

Virchow-Robin space circulation

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.

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].

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). VRS: Virchow Robin space, SAS: subarachnoid space.

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. found no spread of HRP from the subarachnoid space into the VRS [70]. Also, another study reported that following microinjection into the VRS or the subarachnoid space of rats, tracers (e.g. 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. The complex anatomical structure of the Virchow Robin space (VRS) allows a bidirectional fluid exchange between the VRS and both the brain extracellular space (ECS) and the subarachnoid CSF space (blue arrows). 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. A: artery, V: vein, C: capillary, VRS: Virchow Robin space, SAS: subarachnoid space.

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 0.02 μm and 1.0 μm) did not leave the brain but expanded the periarterial spaces and were locally ingested by macrophages. Clearance of solutes along this pathway could be prevented by cardiac arrest [83]. The finding that macromolecules may be drained from the brain via perivascular or intramural transport led to the notion that vessels and their pial sheaths act as ‘lymphatics of the brain’. 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. The deposition of insoluble amyloid may obstruct this drainage pathway and therefore impede the elimination of beta-amyloid and interstitial fluid from the brain in Alzheimer’s disease [82,84]. 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).

Interstitial fluid movement

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.g. polyethylene glycols: 0.9 and 4 kD and albumin: 69 kD), provided evidence for the convection of ISF. 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 0.11 and 0.29 μl g brain -1  min -1 [30,61], reviewed by [29]. Very recently it has been shown that astrocyte water transporters, i.e. aquaporin-4 (AQP4), contribute to interstitial brain water movement: in transgenic animals lacking AQP4, the interstitial drainage of tracer injected into brain parenchyma was significantly reduced [95].

Towards a molecular understanding of brain water fluxes

The discovery of water transporters (‘water channels’) located at the end-feet processes of astrocytes has decisively improved our understanding of the physiology of the blood brain barrier and has led to the concept that large water fluxes take place continuously between the different compartments of the brain, i.e. the blood, CSF and ISF (reviewed in [96-98]). Interestingly, such extensive water movements were indicated by earlier radiotracer experiments. For example in 1952, following the intravenous injection of deuterium oxide a rapid distribution throughout all brain compartments was reported [99]. These data demonstrated water fluxes that greatly exceeded the contemporary estimated rates of CSF and ISF flow. As a result, the significance of this work was not fully appreciated. Recently the original data on the deuterium oxide half-life in different brain compartments has been used to calculate the respective CSF fluxes by applying MRI-based volume assessments of the ventricles, the subarachnoid space and the spinal CSF spaces. As result, CSF fluxes of more than 22 ml min -1 and a CSF turnover rate of more than 140 times a day were calculated. This is far greater than the traditional views of CSF physiology [100]. Of note, the permeability of deuterium oxide through AQP1 [101] and AQP4 [102] is similar to that of water.

Choroid plexus

CSF formation at the choroid plexus occurs in two stages: passive filtration of fluid across the highly permeable capillary endothelium and a regulated secretion across the single-layered choroidal epithelium. The choroidal epithelium forms a fluid barrier since tight junctions are expressed at the apical, CSF facing, cell membrane [103]. The rate of choroidal CSF formation is rather insensitive to osmotic and hydrostatic pressure changes in the CSF and therefore relatively independent of changes in intracranial pressure and plasma osmolarity. Hence, water transport across the choroid plexus epithelium cannot be explained simply by an osmotic mechanism (discussed in detail in [96]). Today there is agreement that choroidal CSF production is controlled by membrane transporters within the epithelium. Different transporters are expressed at the basolateral (plasma facing) and apical (CSF facing) membranes. Due to its high AQP1 expression, the apical membrane has high water permeability. In contrast to this, the basolateral membrane lacks significant AQP1 expression [104]. At the apical membrane a K + /Cl - cotransporter is co-localized with the Na + /K + -ATPase. Together, these transporters expel water from the cell into the CSF space. Little is known about the water transport at the basolateral membrane. There is a K + /Cl - cotransporter, but its role is not yet well understood [96]. The molecular mechanisms of choroidal CSF production are comprehensively reviewed in [96,105,106].

Blood brain barrier

Traditionally the properties of the blood𠄻rain barrier (BBB) are considered to be those of the capillary endothelium in brain. This endothelium contrasts with that elsewhere in the body by being sealed with tight junctions, having a high electrical resistance and a low permeability to polar solutes [89]. Early research unveiled ion channels and transporters capable of providing a net secretion of fluid, driven by Na + /K + - ATPase, on the brain side of the barrier. Accordingly, the BBB was proposed as a secretory endothelium, which produces ISF [107]. Recent research has unveiled that the �rrier’ function of the BBB is in fact the result of highly regulated and complex cellular and molecular transport processes, which allow for the transport of water, solutes, larger molecules and even cells (reviewed by [108-110]). The modern understanding of BBB physiology was further improved by the discovery that cells surrounding the capillaries can control and modulate BBB functions. Considering the involvement of astrocytes, pericytes, microglia and even neurons, the BBB is better described as a ‘neurovascular unit’ [111]. The role of astrocytes is of utmost interest with respect to CSF physiology, since astrocyte end-feet have been shown to cover the entire capillary surface, leaving intercellular clefts of less than 20 nm [112]. The astrocytes, therefore, form an additional barrier surrounding the cerebral capillaries [98]. The role of astrocytes in brain water homeostasis is strongly supported by the finding that water transporting pores (i.e. the aquaporins) are localized in the end feet [113,114], reviewed by [97]. It is also important to recognize that contrary to earlier assumptions, the endothelial barrier carries no AQP4 transporters [115]. Instead, water may cross the endothelium by diffusion, vesicular transport and, even against osmotic gradients, by means of co-transport with ions and glucose (reviewed in [96]).

Aquaporins and other modes of water transport

The physiology of aquaporins (AQPs) and transporters in the brain has been comprehensively reviewed [96,98,116-118]. Here those aspects are discussed, which are relevant for the understanding of CSF circulation. Basically, in response to both passive osmotic and hydraulic pressure gradients, AQPs can transport water, solutes, and ions bi-directionally across a cell membrane. In comparison to diffusional transport, AQPs have significant biophysical differences. Diffusion is non-specific and low-capacity movement, whereas water channels like the AQPs provide rapid transport and have both a high capacity and a great selectivity for the molecules being transported [119]. As discussed below, that may be especially important for fluid exchange between ISF and CSF. More recent data in rodents have demonstrated that the precise dynamics of the astroglia-mediated brain water regulation of the CNS is dependent on the interactions between water channels and ion channels. Their anchoring by other proteins allows for the formation of macromolecular complexes in specific cellular domains (reviewed in [120]).

Currently, at least 14 different aquaporins have been identified [97,117]. At least six have been reported in the brain [121,122]: AQP 1, 4, 5 (specifically water permeable), AQP3 and 9 (permeable for water and small solutes) and AQP8 (permeable for ions) [116]. AQP4 is implicated in the formation/resolution of brain edema and in the clearance of K + released during neuronal activity AQP1 plays a role in cerebrospinal fluid (CSF) formation, and AQP9 may play a role in energy metabolism [97]. Positron emission tomography techniques for imaging of AQP4 in the human brain are currently being developed [123]. Structural and functional data suggests that the permeability of AQP channels can be regulated and that it might also be affected in brain pathologies (reviewed by [116,124]). As a result of the dynamic regulation, AQP channel permeability or AQP channel subcellular localization may change within seconds or minutes leading to immediate changes in the membrane permeability. Long-term regulation is mediated by changes in AQP mRNA and/or protein synthesis and/or degradation rate. These changes will alter AQP expression within hours or days. AQPs may be regulated under pathological conditions: For example AQP1 and AQP4 are strongly upregulated in brain tumors and in injured brain tissue [116], AQP5 is down-regulated during ischemia but up-regulated following brain injury [121].

Notably, AQP1 is expressed in vascular endothelial cells throughout the body but is absent in the cerebrovascular endothelium, except in the circumventricular organs [125]. As already discussed AQP1 is found in the ventricular-facing cell plasma membrane of choroid plexus epithelial cells suggesting a role for this channel in CSF secretion. In AQP1-null mice, CSF production was 20% less than in wild-type mice (0.38 ±𠂐.02 vs. 0.30 ±𠂐.01 μl min -1 ). Accordingly it was discussed that AQP1-facilitated transcellular water transport accounts for only part of the total choroidal CSF production. As a more controversial possibility, it was suggested that the choroid plexus may not be the principal site of CSF production and that extrachoroidal CSF production by the brain parenchyma may be more important [126,127]. The latter notion is supported by the observation that following its intravenous application, the penetration and steady concentration of H2 17 O is significantly reduced in ventricular CSF in AQP4 but not in AQP1 knockout mice. The authors concluded that AQP4 is more important for CSF production than AQP1 [122,128].

AQP4 is strongly expressed in astrocyte foot processes at the BBB, glia limitans of brain surface and VRS, as well as ventricular ependymal cells and subependymal astrocytes. Actually, it is expressed at all borders between brain parenchyma and major fluid compartments [97,113,114]. Therefore, the earlier view of exchange of ISF and CSF across ependymal and glial cell layers [129] may be in fact aquaporin-mediated water transport across these membranes [130]. AQP4 is also localized in astrocyte end feet at the perisynaptic spaces of neurons and is found in the olfactory epithelium [97]. The precise subcellular distribution of AQP4, i.e. in the astrocyte foot processes, is regulated by its association with the dystrophin glycoprotein complex, including dystrophin, beta-dystroglycan, and syntrophin [131,132]. In mice lacking alpha-syntrophin, astrocyte AQP4 is displaced, being markedly reduced in the end feet membranes adjacent to the blood vessels in cerebellum and cerebral cortex, but present at higher than normal levels in membranes directly facing the neuropil [131]. Others reported that the deletion of alpha-syntrophin causes a 50% loss of AQP4 from the cortical membrane as compared with a 90% loss at the perivascular membrane [133]. A similar effect on AQP4 localization is observed in dystrophin-null mice [134]. AQP4 has been suggested to interact with the inwardly rectifying K + channel Kir4.1 [135]. Since Kir4.1 is also associated with the dystrophin glycoprotein complex the pattern of the subcellular distribution of AQP4 and Kir4.1 in astrocytes is very similar [136].

AQP4 is involved in water movements under pathological conditions (see for details [97,125,137,138]). There is agreement that AQP4-null mice have reduced brain swelling and improved neurological outcome in models of (cellular) cytotoxic cerebral edema including water intoxication, focal cerebral ischemia, and bacterial meningitis. However, brain swelling and clinical outcome are worse in AQP4-null mice in models causing a disruption of the BBB and consecutive vasogenic edema. Impairment of AQP4-dependent brain water clearance was suggested as the mechanism of injury in cortical freeze-injury, brain tumor, brain abscess and hydrocephalus [125]. In hydrocephalus produced by cisternal kaolin injection, AQP4-null mice demonstrated ventricular dilation and raised intracranial pressure, which were both significantly greater when compared to wild-type mice [139].

It is a matter of ongoing research whether AQP4-mediated brain water movement is relevant under physiological conditions. Considering only the pattern of AQP4 expression at the borders between the brain and CSF compartments, it has been suggested that AQP4 facilitates or controls the flow of water into and out of the brain [98]. However, how aquaporins modulate CSF/ISF circulation and whether they impact fluid flow in extracellular pathways within the tightly packed neuropil is only poorly understood. Since AQP4 is also expressed at astrocytic end feet near the perisynaptic spaces, a putative role for astrocytes and AQP4 for K + homeostasis during neuronal activity has been postulated (reviewed by [97]). AQP4 deletion is associated with a sevenfold reduction in cell plasma membrane water permeability in cultured astrocytes [140] and a tenfold reduction in BBB water permeability in mouse brain [141]. However, AQP4 deletion was found to have little impact on CSF dynamics (reviewed by [106]). In AQP4-null mice unaltered intracranial pressure and compliance were found [142]. Furthermore, no changes in ventricular volume or anatomical features of two different AQP4-null mice strains were reported [143]. However, others observed smaller ventricular sizes, reduced CSF production and increased brain water in AQP4-null mice [144]. Considering that the deletion of AQP4 has only little or modest in vivo effects, the current view is that, under normal physiological conditions, AQP4 is not needed for relatively slow water movement conditions [97]. However, the minimal impact of AQP4 deletion on CSF physiology may be explained by the fact that AQP4 deletion reduces both ISF/CSF formation and absorption. Mice in which a conditional knockout was driven by the glial fibrillary acidic protein promoter, showed increased basal brain water content. In these animals the extracerebral AQP4 function is preserved but AQP4 is eliminated in cells that express the GFAP promoter, i.e., astrocytes and ependyma. After systemic hypo-osmotic stress by intraperitoneal water injection, those mice showed a 31% reduction in brain water uptake. It was concluded that the glial covering of the neurovascular unit limits the rate of brain water influx as well as the efflux [115].

It is now widely accepted that water moves across the endothelium by simple diffusion and vesicular transport, and across the astrocyte foot process primarily through AQP4 channels (reviewed by [98]). In addition, a variety of endothelial water-transport proteins expressed in one or both of the cell membranes (luminal or apical), provide co-transport of water along with their substrates even independently of osmotic gradients. Especially the glucose transporter GLUT1 and the Na + /K + /2Cl - cotransporter, NKCC1, may contribute significantly to transendothelial water transport (reviewed by [96]). The identification of non-aquaporin water transporters located at the endothelium was a major contribution to the understanding of water transport across the neurovascular unit (not just the astrocyte or endothelial barrier). It is important to recognize that all these transport mechanism are bi-directional and represent a dynamic process. This implies that large water fluxes may take place continuously, although the net flow may be small. This would explain the fast and extensive passage of deuterium oxide from blood to brain [99]. As a process independent of net flow, the finding could be understood as a result of a dynamic bidirectional mixing of water between the blood, ISF and the CSF compartments. The bidirectional transport could also generate net-flux. Actually, the neurovascular unit may not only be involved in the production but also in the absorption of CSF and ISF. This is suggested by recent experiments in which tritiated water was infused into the ventricle of cats. During a three-hour infusion, the concentration in blood sampled from the cerebral venous sinuses rapidly increased up to 5 times higher than in samples of cisternal CSF and arterial blood. However, following the infusion of 3 H-inulin, the cisternal concentration increased sharply during the observation period of three hours. At the same time venous and arterial concentrations were near background activity. It was concluded that 3 H-water, but not 3 H-inulin, is absorbed from brain ventricles into periventricular capillaries, which eventually drain in the venous sinuses [145]. Figures  2 and ​ and3 3 illustrate that aquaporins, associated with astrocytes in the glial and ependymal cell layers, may control brain water movement around the Virchow Robin space and across the brain compartments.

Diagram of the CSF "Circulation". This diagram summarizes fluid and cellular movements across the different barriers of the brain compartments (blood, interstitial fluid, Virchow Robin space, cerebrospinal fluid space comprising the cerebral ventricles, basal cisterns and cortical subarachnoid space). Aquaporins and other transporters control the fluid exchange at the glial, endothelial, and choroid plexus barrier. At the glial, endothelial, and pial barrier bi-directional flow may generate either a net in- or outflux, providing fluid exchange rates, which surpass the net CSF production rate by far. The choroid plexus is the only direct connection between the blood and the CSF compartment. Major portions of brain water are drained into the cervical lymphatics from the VRS (including its capillary section) via intramural arterial pathways (asterisks) and from the CSF space (via perineural subarachnoid space of cranial nerves). The capillary and venular endothelium may contribute to brain water absorption. Blood borne inflammatory cells may enter the brain via VRS venules or via CP. Fluid movements at the barriers are driven by osmotic and hydrostatic gradients or by active transporter processes. Fluid movements into and out of the VRS depend on respiratory and cardiac pressure pulsations.

Magnetic resonance flow studies

Phase-contrast magnetic resonance imaging (MRI) can provide quantitative blood flow velocity information in humans [146]. It was applied to the study of CSF flow along the aqueduct, a small canal connecting the third and fourth cerebral ventricles [147,148]. Advanced phase-contrast MRI, the cine phase-contrast technique yields quantitative flow information by synchronizing the acquisition of the images to the cardiac cycle [149]. Eventually, these MRI techniques may be applied to assess the heartbeat related stroke volume of CSF, from which the CSF net flow along the aqueduct may be calculated [150]. Applying these techniques, the normal aqueduct flow has been measured many times in adults with flow rates ranging from 0.304 to 1.2 ml min -1 [151-155]. Based upon these data, the average normal flow in healthy adults was suggested to be 0.77 ml min -1 in the craniocaudal direction [7]. Hence, CSF flow measured by MRI exceeds the customarily assumed choroidal CSF production rate by two fold. Findings showing a reversed (caudocranial) flow of CSF along the aqueduct are even more puzzling. A reversed flow of 0.41 ±𠂐.51 ml min -1 was reported in children younger than two years [7]. Furthermore, a reversed flow was reported in adult patients suffering from normal pressure hydrocephalus: mean stroke volume in the control group was 30.1 ±�.8 μl/cycle (craniocaudal direction), while that in the NPH group it was -63.2 ±�.0 μl/cycle (caudocranial direction) [156]. In NPH patients, similar observations were reported by others [152]. Technical limitations of the MRI flow measurements must be considered before interpreting these MRI data that are not congruent with the traditional understanding of CSF physiology. Thus it was pointed out that the evaluation of the flow void is subjective and highly dependent on the acquisition parameters used, as well as on the technical characteristics of the MR imaging systems (e.g. gradient strength) [147]. Unfortunately, there is no class A evidence reported, which would clarify these conflicting data. Appropriate clinical studies would be important. Also, MRI techniques may be used to study interstitial water movement: diffusion-weighted MRI provides a quantitative parameter, i.e. the apparent diffusion coefficient (ADC), which is thought to reflect water mobility in brain tissues. Applying this technique it was shown in the rat brain that reducing AQP4 protein expression with small interfering RNAs (siRNAs) by 27% caused a 50% decrease of the ADC [157].

Current research

There are numerous limitations of the early experiments that form our classical understanding of CSF physiology. Recent progress in neuroanatomy, molecular and cellular biology, and neuroimaging challenge the traditional model. The pillars of the classical model, i.e. CSF production at the choroid plexus, directed bulk flow and absorption across the arachnoid villi are currently being questioned. More recent experimental and clinical data have caused a growing number of researchers to reach the consensus that ISF and CSF are mainly formed and reabsorbed across the walls of CNS blood capillaries, which implies that there is no need for a directed CSF circulation from CP to the arachnoid villi. Eventually, a number of "unequivocal" findings, often more than 100 years old and still governing the customary understanding of CSF physiology, must be revised [7,9,10,88,95,98,122,158,159].

However, the novel concepts are also challenged mainly by the lack of validated supporting data. For example, Klarica et al. failed to reproduce the historical experiments of Dandy [13], since no circulation of CSF was found along a plastic cannula introduced into the aqueduct of cats [16]. Subsequent experiments demonstrated that the CSF pressure is not increased during the first hours after the occlusion of aqueduct of Sylvius [160]. Since they furthermore showed that following its intraventricular injection radioactive water is almost completely absorbed in the ventricles and does not reach the basal cisterns [145], they concluded that the choroid plexus is not the major site of CSF production and that no directed CSF circulation according to the classical understanding exists. Instead they proposed a model that assumes CSF production and absorption occurs at the level of the capillaries [10]. Considering the existence of CSF flow along the aqueduct as shown by MRI flow studies, others recognized that a model assuming CSF flow exclusively at the capillary bed is deficient [7]. Furthermore the view of Klarica et al. that CSF production and absorption just depend on hydrodynamic and osmotic gradients is not substantiated by current cellular and molecular biology findings. In fact, the proposed model does not consider the complex regulation of water movement between the brain compartments as discussed above. Finally, as in the original experiments of Dandy, the experiments of Klarica et al. may be criticized since they are surgically invasive and therefore results should be interpreted cautiously.

There are similar concerns with the most recent publications of Nedergaard and her group. In a series of experiments, fluorescent tracers of different molecular weight were injected into the cisterna magna of mice [95]. Applying two-photon laser scanning microscopy through a closed cranial window, the distribution of tracers could be observed 60� μm below the cortical surface. The experiments showed a rapid increase of fluorescence within the Virchow Robin space around the arterioles. Fluorescent tracer was subsequently found within the brain interstitium and later around the venules. Histological examination 30 minutes after cisternal fluorescent tracer injection revealed that larger molecular tracer (FITC-d2000, 2000 kD) was confined to the VRS, while smaller molecular weight tracer (TR-d3, 3 kD) was concentrated in the VRS and also entered the interstitium. Investigating AQP4-deficient mice with the same experimental techniques, the authors found significantly less fluorescence within both, the VRS around the arteries and in the brain interstitium [95]. Considering the temporospatial occurrence of fluorescence, the authors deduced the existence of a directed flow of CSF from the subarachnoid space along the arteries and arterioles into the VRS, from here into the brain interstitium, and finally from the brain into the VRS around the venous vessels. Since the authors showed in AQP4 deficient mice that, following its interstitial injection, the clearance of soluble amyloid beta was significantly reduced, they concluded to have discovered an unknown system for the clearing of interstitial protein waste [88,161]. Assuming the PVS to serve as lymphatics of the brain (a notion which was conceptualized already in 1968 by Foldi [162]) and considering the involvement of astrocytes and their aquaporins the authors coined the term "glymphatics" to describe the system [95].

It should be noted that the glymphatic concept assumes transport from the SAS INTO the parenchyma along periarterial pathways. This notion is supported by previous findings of Rennels et al.[73]. However, as already discussed above, especially the work of the groups of Cserr [94] and Weller [45,70] support the view that the periarterial flow provides a drainage OUT of the parenchyma. Furthermore the findings of Nedergaard’s group are not consistent with previous work applying real-time video-densiometric techniques. Such experiments have depicted the movement of tracers within the VRS to be sluggish and the direction of flow varying in an unpredictable manner [71]. Currently, it is difficult to come to final conclusions about the direction of perivascular CSF flow. This is a complex research topic with difficult, technically challenging experiments not easily replicated among the different groups.

Regarding the glymphatic concept, one may criticize that it is based on two-photon laser scanning microscopy applying a 1 min scan time, which was optimized to acquire a 240 μm stack at 20 μm intervals. This appears to be a limitation of the scanning technique in terms of temporal resolution. It seems important to provide data with higher frequency imaging to clarify the direction of perivascular flow [71]. Furthermore, with the published data, it can’t be excluded that the observed fluorescence around subarachnoid arteries may reflect the nonspecific binding of dextran to the basement membranes of arteries [87]. Considering these criticisms and the point that the glymphatic concept represents a fundamental revision of the current understanding of CSF physiology, we feel that the concept needs to be substantiated by comprehensive ultrastructural investigations. Also studies in other species are warranted.

A subsequent publication of Nedergaard’s group reports the exciting possibility of an increased clearance rate of brain waste along the glymphatic pathway during sleep [163]. 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.e. arterial blood pressure, venous blood pressure, stress hormone blood levels, heart and respiratory rate and blood gases. 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]. Each of these parameters may in turn influence ISF and CSF circulation and the width of the interstitial space.

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. [95] revive the work of Cserr [30], who showed that bulk flow mechanisms contribute to the clearance of tracers injected into the brain interstitium. Confirmatory evidence of the impact of aquaporins on ISF regulation has been independently reported by others [115].


Cerebrospinal fluid

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Cerebrospinal fluid (CSF), clear, colourless liquid that fills and surrounds the brain and the spinal cord and provides a mechanical barrier against shock. Formed primarily in the ventricles of the brain, the cerebrospinal fluid supports the brain and provides lubrication between surrounding bones and the brain and spinal cord. When an individual suffers a head injury, the fluid acts as a cushion, dulling the force by distributing its impact. The fluid helps to maintain pressure within the cranium at a constant level. An increase in the volume of blood or brain tissue results in a corresponding decrease in the fluid. Conversely, if there is a decrease in the volume of matter within the cranium, as occurs in atrophy of the brain, the CSF compensates with an increase in volume. The fluid also transports metabolic waste products, antibodies, chemicals, and pathological products of disease away from the brain and spinal-cord tissue into the bloodstream. CSF is slightly alkaline and is about 99 percent water. There are about 100 to 150 ml of CSF in the normal adult human body.

The exact method of the formation of the CSF is uncertain. After originating in the ventricles of the brain, it is probably filtered through the nervous-system membranes (ependyma). The CSF is continually produced, and all of it is replaced every six to eight hours. The fluid is eventually absorbed into the veins it leaves the cerebrospinal spaces in a variety of locations, including spaces around the spinal roots and the cranial nerves. Movement of the CSF is affected by the downward pull of gravity, the continual process of secretion and absorption, blood pulsations in contingent tissue, respiration, pressure from the veins, and head and body movements.

Examination of the CSF may diagnose a number of diseases. A fluid sample is obtained by inserting a needle into the lumbar region of the lower back below the termination of the spinal cord this procedure is called a lumbar puncture or spinal tap. If the CSF is cloudy, meningitis (inflammation of the central nervous system lining) may be present. Blood in the fluid may indicate a hemorrhage in or around the brain.


Enhance Cerebrospinal Fluid Flow Naturally

The brain and spinal cord make up the central nervous system (CNS) which is the master control system for the entire body. It sends and receives a complicated frequency of signals with the body that dictate the function of the tissues & cells. The cerebrospinal fluid (CSF) bathes, feeds, & protects the brain and spinal cord (1).

The CSF maintains the electrolytic environment of the central nervous system by cleansing metabolic waste products from the brain and spinal cord. This rinsing process also plays a large role in stabilizing the critical acid-base balance throughout the CNS (2).

It also provides valuable supply of essential nutrients to neuronal and glial cells. CSF also provides a medium to transport hormones, neurotransmitters, releasing factors, and other neuropeptides (3).

CSF Stasis & Vertebral Subluxation:

When the CSF flow becomes stagnant it is classically referred to as CSF stasis. CSF stasis has been associated with vertebral subluxation complex, mechanical tension on the spinal cord, reduced cranial rhythmic impulses & restricted respiratory function. Reduced rates of CSF diffusion through key regions of the brain are a causative factor involved in degenerative disease (4, 5).

The CSF has two major pumps that help to establish healthy flow. The pump at the top of the spine is the occiput bone which makes up the lower portion of the skull. Flexion and extension motions of the occipital bone upon the atlas help to pump CSF through the brain and spinal cord (6, 7).

The other pump is at the bottom of the spine in the sacrum. Flexion and extension of the sacrum is also critical to help pump the CSF.

Sedentary Lifestyles and CSF Stasis:

Sedentary lifestyles and bad postural habits create an environment ripe for CSF stasis in the spinal cord. Sedentary lifestyles create poor core strength and muscle imbalances that lead to chronic subluxation patterns throughout the spine. Sitting for long periods contributes to poor sacral motion and accelerated degenerative changes in the lumbo-pelvic region.

Sedentary lifestyles and poor posture contribute to the formation of forward head posture. Forward head posture is characterized by occipital bone subluxation patterns. The majority of these subluxations have the occiput stuck into extension on the atlas bone with dense ligamentous scar tissue. This is also the most subluxation pattern found in whiplash like traumas.

Corrective Chiropractic Improves CSF:

Healthy CSF flow depends upon a continual approach to minimize subluxation through corrective chiropractic techniques and specific spinal exercises. Chiropractic adjustments are designed to release the ligamentous scar tissue that is locking the region in place (8, 9).

This allows for better neurological function through healthy proprioceptive patterns (10). Additionally, these adjustments help reinforce healthy soft tissue formation in the subluxated regions. This new healthy tissue will allow these regions to have normal, healthy motion.

Wobble Board Exercises:

Wobble board exercises help to restore and reinforce healthy sacral movement and initiate the CSF pump. The wobble board has a very small center of gravity that creates a greater challenge to the coordinating centers of the brain.

This results in increased receptor information from the sacral region that allows a greater degree of range of motion and a further CSF pumping effect. As little as 2-3 minutes of wobble board exercises can have a dramatic effect on the CSF pump.

You can find a wobble board here and a wobble chair here

Repetitive Cervical Traction Exercises:

Repetitive cervical traction exercises puts motion into the occipital region. This motion helps to traction the occiput creating a pressure change which helps facilitate the CSF pump. This allows cleaner CSF to flow into the brain stem region providing fresh oxygen and nutrition.

Additionally, the traction helps stretch chronically tight upper cervical muscles and ligaments and allows new tissue to form with greater elasticity.

It is advisable for individuals to take regular ergonomic breaks to get up and stretch and perform these exercises. This will allow the individual to improve CSF flow which will improve neurotransmitter function, concentration and mental acuity.

You can find the cervical traction unit I use here


Watch the video: Νευρικό Σύστημα. Μέρος Γ: Εγκέφαλος και Νωτιαίος Μυελός (July 2022).


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