Protection of the Brain

Blood-Brain Barrier

Tight junctions present in the blood-brain barrier separate circulating blood from cerebrospinal fluid, regulating diffusion into the brain.

Learning Objectives

Describe the function of the blood-brain barrier

Key Takeaways

Key Points

  • The blood – brain barrier (BBB) endothelial cells restrict the passage of substances from the bloodstream to a greater extent than endothelial cells in capillaries elsewhere in the body.
  • The BBB results from the selectivity of the tight junctions between endothelial cells in central nervous system (CNS) vessels that restrict the passage of solutes.
  • Several areas of the human brain are not protected by the BBB, including the circumventricular organs.
  • Tight junctions are composed of transmembrane proteins such as occludin and the claudins.
  • The BBB effectively protects the brain from many common bacterial infections. However, since antibodies and antibiotics are too large to cross the BBB, infections of the brain that do occur are often difficult to treat.

Key Terms

  • astrocyte: A star-shaped neuroglial cell.
  • claudins: This family of proteins is the most important component of tight junctions, where they establish the paracellular barrier that controls the flow of molecules in the intercellular space between the cells of an epithelium.
  • blood-brain barrier: A structure in the CNS that keeps substances found in the bloodstream out of the brain while allowing in substances essential to metabolic function such asoxygen.
  • occludin: A protein forming the main component of the tight junctions, along with the claudin group of proteins.

Examples

  • An exception to the bacterial exclusion are the diseases caused by spirochetes, such as Borrelia, which causes Lyme disease, and Treponema pallidum, which causes syphilis. These harmful bacteria seem to breach the BBB by physically tunneling through the blood vessel walls.
  • Modalities for drug delivery through the BBB entail its disruption by osmotic means, biochemically by the use of vasoactive substances, or by localized exposure to high-intensity focused ultrasound.

The blood-brain barrier (BBB) is a separation of circulating blood from the brain extracellular fluid in the central nervous system (CNS). Bacteriologist Paul Ehrlich observed that chemical dye injected into an animal would stain all of its organs except for the brain. In a later experiment, his student Edwin Goldmann found that when dye is directly injected into the cerebrospinal fluid (CSF) of animals’ brains, the brains were dyed while the rest of the organs were unaffected. This clearly demonstrated the existence of some sort of compartmentalization between the brain and the rest of the body. The concept of the BBB (then termed hematoencephalic barrier) was proposed by Lewandowsky in 1900. It was not until the introduction of the scanning electron microscope that the actual membrane could be observed and proven to exist.

Blood-Brain Barrier Structure

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The Blood Brain Barrier at the Small Scale: Astrocytes send projections to completely encircle capillaries. This allows tight regulation of passage of molecules into and out of the CNS.

The BBB results from the selectivity of the tight junctions between endothelial cells in CNS vessels that restrict the passage of solutes. At the interface between blood and the brain, endothelial cells are joined by these tight junctions, which are composed of smaller subunits, frequently biochemical dimers that are transmembrane proteins such as occludin, claudins, and junctional adhesion molecule. Each of these transmembrane proteins is anchored into the endothelial cells by another protein complex. This barrier also includes a thick basement membrane and astrocyte cell projections called astrocytic feet (forming the thin barrier called the glia limitans) that surround the endothelial cells of the BBB, providing biochemical support to those cells.

Function and Importance of the Blood-Brain Barrier

The BBB endothelial cells restrict the passage of substances from the bloodstream to a greater extent than endothelial cells in capillaries elsewhere in the body. The diffusion of microscopic particles (e.g., bacteria), large molecules, and hydrophilic molecules into the CSF is restricted, while the diffusion of small hydrophobic molecules (O2, CO2, hormones ) is permitted. Also, BBB cells actively transport metabolic products such as glucose across the barrier.

Non-Protected Areas of the Brain

Several areas of the human brain are not protected by the BBB. These include the circumventricular organs such as the area postrema, median eminence of the hypothalamus, pineal gland, and the posterior pituitary. The posterior pituitary and pineal gland are not covered by the BBB because they secrete hormones into circulation. The median eminence is not covered by BBB because the pituitary secretions collect in this area before release into circulation. The area postrema detects noxious substances present in the blood and is therefore not covered by the BBB.

Role of Blood-Brain Barrier in Infectious Processes

The BBB effectively protects the brain from many common bacterial infections, so brain infections are very rare. However, since antibodies and antibiotics are too large to cross the BBB, brain infections that do occur are often very serious and difficult to treat. However, the BBB becomes more permeable during inflammation. This allows some antibiotics and phagocytes to move across the BBB, but also allows bacteria and virus to cross. Diseases caused by spirochetes are exceptions to this bacterial exclusion. These include Borrelia (the cause of Lyme disease), and Treponema pallidum, which causes syphilis. These harmful bacteria seem to breach the BBB by physically tunneling through the blood vessel walls. Some toxins are made up of large molecules that cannot pass through the BBB. Neurotoxins such as botulinum toxin in food might affect peripheral nerves, but the BBB can often prevent such toxins from reaching the CNS, where they could cause serious or fatal damage.

Cerebrospinal Fluid and Its Circulation

Cerebrospinal fluid is a clear fluid that acts as a cushion for the brain and maintains overall central nervous system homeostasis.

Learning Objectives

Describe the role and circulation of cerebrospinal fluid in the nervous system

Key Takeaways

Key Points

  • Cerebrospinal fluid (CSF) is a clear, colorless bodily fluid that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord.
  • CSF acts as a cushion or buffer for the cortex, providing a basic mechanical and immunological protection to the brain inside the skull and serving a vital function in cerebral autoregulation of cerebral blood flow.
  • CSF serves five primary purposes: buoyancy, protection, chemical stability, waste removal, and prevention of brain ischemia.
  • CSF can be tested for the diagnosis of a variety of neurological diseases through the use of a procedure called lumbar puncture.
  • CSF is produced in the choroid plexus in the brain by modified ependymal cells.

Key Terms

  • glymphatic system: Functional waste clearance pathway for the vertebrate central nervous system (CNS) that consists of a para-arterial influx route for CSF to enter the brain coupled to a clearance mechanism for the removal of interstitial fluid and extracellular solutes from the interstitial compartments of the brain and spinal cord.
  • choroid plexus: A structure in the ventricles of the brain where CSF is produced.
  • lumbar puncture: A diagnostic and at times therapeutic procedure performed to collect a CSF for biochemical, microbiological, and cytological analysis, or rarely to relieve increased intracranial pressure.

Examples

A 2010 study showed that analysis of CSF for three protein biomarkers can indicate the presence of Alzheimer’s disease. The three biomarkers are CSF amyloid beta 1-42, total CSF tau protein, and P-Tau181P. In the study, the biomarker test showed good sensitivity, identifying 90% of persons with Alzheimer’s disease, but poor specificity, as 36% of control subjects were positive for the biomarkers. The researchers suggested that the low specificity may be explained by developing but not yet symptomatic disease in controls.

Cerebrospinal fluid (CSF) is a clear, colorless bodily fluid that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord. The CSF occupies the space between the arachnoid mater (the middle layer of the brain cover, the meninges ) and the pia mater (the layer of the meninges closest to the brain). It constitutes the content of all intracerebral ventricles, cisterns, and sulci (singular sulcus), as well as the central canal of the spinal cord. It acts as a cushion or buffer for the cortex, providing a basic mechanical and immunological protection for the brain inside the skull and serving a vital function in cerebral autoregulation of cerebral blood flow.

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.

This diagram of the subarachnoid cavity of the brain indicates the meningeal vein, diploic vein, venous lacuna, emissary vein, cerebral vein, superior sagittal sinus, arachnoid granulation, dura mater, arachnoid, cerebral cortex, falx cerebri, pia mater, subdural cavity, and subarachnoid cavity.

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.

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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.

Functions of CSF

The functions of CSF include:

  1. Buoyancy: The actual mass of the human brain is about 1400 grams; however, the net weight of the brain suspended in the CSF is equivalent to a mass of 25 grams. The brain therefore exists in neutral buoyancy, which allows the brain to maintain its density without being impaired by its own weight.
  2. Protection: CSF protects the brain tissue from injury when jolted or hit.
  3. Chemical stability: CSF flows throughout the inner ventricular system in the brain and is absorbed back into the bloodstream, rinsing the metabolic waste from the central nervous system (CNS) through the blood-brain barrier. This allows for homeostatic regulation of the distribution of neuroendocrine factors, to which slight changes can cause problems or damage to the nervous system.
  4. Prevention of brain ischemia: Decreasing the amount of CSF in the limited space inside the skull decreases total intracranial pressure and facilitates blood perfusion.
  5. Clearing waste: CSF has been shown by the research group of Maiken Nedergaard to be critical in the brain’s glymphatic system, the functional waste clearance pathway for the vertebrate CNS.

CSF as a Diagnostic Tool

When CSF pressure is elevated, cerebral blood flow may be constricted. When disorders of CSF flow occur, they may therefore affect not only CSF movement but also craniospinal compliance and intracranial blood flow, with subsequent neuronal and glial vulnerabilities. The venous system is also important in this equation. CSF can be tested for the diagnosis of various neurological diseases, usually with a procedure called lumbar puncture. Lumbar puncture is performed in an attempt to count the cells in the fluid and to detect the levels of protein and glucose. These parameters alone may be extremely beneficial in the diagnosis of subarachnoid hemorrhage and CNS infections such as meningitis. Moreover, a CSF culture examination may yield the microorganism that has caused the infection.

Ventricles

The ventricular system is a set of hollow cavities in the brain filled with cerebrospinal fluid.

Learning Objectives

Describe the function and locations of the ventricles in the brain

Key Takeaways

Key Points

  • The ventricular system is continuous with the central canal of the spinal cord.
  • The ventricles are filled with cerebrospinal fluid (CSF), which bathes and cushions the brain and spinal cord within their bony confines.
  • CSF flows from the lateral ventricles via the foramina of Monro into the third ventricle.
  • CSF flows from the third ventricle to the fourth ventricle via the cerebral aqueduct in the brainstem.
  • CSF flows from the fourth ventricle into the central canal of the spinal cord or into the cisterns of the subarachnoid space via three small foramina: the central foramen of Magendie and the two lateral foramina of Luschka.
  • The cerebral aqueduct and the foramina are very small and easily blocked, which would cause high pressure in the lateral ventricles and hydrocephalus.

Key Terms

  • cerebrospinal fluid (CSF): A clear, colorless bodily fluid produced in the choroid plexus of the brain that acts as a cushion or buffer for the cortex, providing a basic mechanical and immunological protection to the brain inside the skull.
  • cerebral aqueduct: The channel in the brain which connects the third ventricle to the fourth ventricle. Also called the aqueduct of sylvius. It is surrounded by the periaqueductal gray.
  • lateral foramina of Luschka: Also known as the lateral aperture, an opening in each lateral extremity of the fourth ventricle of the human brain that provides a conduit for cerebrospinal fluid to flow from the brain’s ventricular system into the subarachnoid space.

Examples

In the late 1970s, CT scans of the ventricles revolutionized the study of mental disorders. Researchers found that on average, individuals with schizophrenia had enlarged ventricles compared to healthy subjects. This became the first evidence that mental disorders are biological in origin and led to a reinvigoration of the study of such conditions via modern scientific techniques.

The ventricular system is a set of four interconnected cavities (ventricles) in the brain and the location of CSF production. This system is continuous with the central canal of the spinal cord. The system comprises four ventricles:

  • right and left lateral ventricles (the first and second ventricles)
  • third ventricle
  • fourth ventricle

CSF Production

The cavities of the cerebral hemispheres are called lateral ventricles or first and second ventricles. These two ventricles open into the third ventricle by a common opening called the foramen of Monro. CSF is produced by modified ependymal cells of the choroid plexus found in all components of the ventricular system except for the cerebral aqueduct and the posterior and anterior horns of the lateral ventricles. The brain and spinal cord are covered by a series of tough membranes called meninges, which protect these organs from rubbing against the bones of the skull and spine. The CSF within the skull and spine is found between the pia mater and the arachnoid and provides further cushioning. EndFra

CSF Flow Within Ventricles

CSF flows from the lateral ventricles via the foramina of Monro into the third ventricle, and then into the fourth ventricle via the cerebral aqueduct in the brainstem. From there, it passes into the central canal of the spinal cord and into the cisterns of the subarachnoid space via three small foramina: the central foramen of Magendie and the two lateral foramina of Luschka. The fluid then flows around the superior sagittal sinus to be reabsorbed via the arachnoid villi into the venous system. CSF within the spinal cord can flow all the way down to the lumbar cistern at the end of the cord around the cauda equina.

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Brain Ventricles: Lateral and anterior views of the brain ventricles, including the third and fourth ventricle, lateral ventricles, interventricular foramen, cerebral aqueduct, and central canal.

Ventricular System Dysfunction and Disease

Diseases of the ventricular system include abnormal enlargement (hydrocephalus) and inflammation of the CSF spaces (meningitis, ventriculitis) caused by infection or introduction of blood following trauma or hemorrhage. The aqueduct between the third and fourth ventricles is very small, as are the foramina. This means they can be easily blocked, causing high pressure in the lateral ventricles. This is a common cause of hydrocephalus (known colloquially as “water on the brain”), an extremely serious condition due to the damage caused by the pressure as well as the nature of the block (e.g., a tumor or inflammatory swelling).

Embryonic Development of the Ventricles

The structures of the ventricular system are embryologically derived from the center of the neural tube (the neural canal). As the future brain stem aspect of the primitive neural tube develops, the neural canal expands dorsally and laterally, creating the fourth ventricle.  The cerebral aqueduct is formed from the part of the neural canal that does not expand and remains the same at the level of the midbrain superior to the fourth ventricle. The fourth ventricle narrows at the obex, where the fourth ventricle narrows to become the central canal in the caudal medulla.