Neuroscience Nursing: Evidence-Based Theory and Practice

By Sue Woodward

“Superior… An important resource for nurses”

Shanne McNamara, Vice President, British Association of Neuroscience Nurses

Neuroscience Nursing is a comprehensive, practical text that reflects both the richness and the diversity of contemporary neuroscience nursing. It aims to inform the practice of neuroscience nursing through the report of current research, best available evidence, policy and education.

This important new book is divided into several sections exploring anatomy and physiology of the nervous system; assessment, interpretation and management of specific problems in the neurological patient; neurological investigations and neurosurgical procedures; management of patients with intracranial disorders; and management of patients with long-term conditions. It also explores the underpinning concepts of neuroscience care, including its history and development, and legal and ethical issues. Uniquely, this text also includes patients’ perspectives of living with a variety of neurological conditions.

Key features:

• The first evidence-based UK neuroscience textbook for nurses
• Extensive full colour illustrations throughout
• Applicable to a wide variety of settings including prevention, primary care, acute and critical care, rehabilitation and palliative care
• Contributions from nurse specialists, nurse consultants, academics and subject experts from throughout the UK

• Language: English
• Publisher: Wiley
• Release date: Dec 1, 2010
• ISBN: 9781444329186

Book preview

Section I: Anatomy and Physiology of the Nervous System

1

Cells of the CNS and How They Communicate

Colm Treacy

INTRODUCTION

The neurone (or nerve cell) is the most important component of the nervous system. Its main function is to rapidly process and transmit information. The human nervous system contains about 300–500 billion neurones (approximately 80,000/mm²), integrated into an intricate functional network by millions of connections with other neurones. Neurones communicate primarily via chemical synapses. The action potential is the fundamental process underlying synaptic transmission. It occurs as a result of waves of voltage that are generated by the electrically excitable membrane of the neurone.

This chapter will explore the histology of the nervous tissue and the physiology of neurotransmission.

COMPONENTS OF THE NEURONE AND THEIR FUNCTIONS

Neurones contain components and organelles that are crucial to normal cellular function and these generally resemble those of non-neuronal cells. Neurones of various types have different morphologies and functional features, depending on their location in the central nervous system (CNS). The prototypical neurone (Figure 1.1) consists of a stellate cell body (soma), a single axon that emerges from the soma, a number of thin processes called dendrites (the axon and dendrites are collectively known as neurites) and points of functional contact at the axon terminal with other cells, glands or organs, called synapses. The integrative functions of these unique structures are what differentiate neurones from non-neuronal cells and underlie the generation and transmission of information, which is so unique and fundamental to nervous system activity.

Figure 1.1 Diagram of a multipolar neurone. Note that the processes of other neurones make synaptic contacts with it. Synapses may be formed, as illustrated, with the soma or with the dendrites, although other types of synapses also occur.

Reproduced from Maria A Patestas and Leslie P Gartner, A Textbook of Neuroanatomy, Wiley-Blackwell, with permission.

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Like other cells in the body, the neurone is enclosed by a bi-layered lipoprotein-rich cell membrane, called the neuronal membrane. This membrane is approximately 5–7.5 nm thick and separates the cytoplasmic contents from the extracellular environment.

As in non-neuronal cells, the soma, (or cell body, also known as the perikaryon), is roughly spherical in shape and measures around 20 µm in diameter. The soma of smaller neurones may measure as little as 5 µm, whereas in the case of large motor neurones, they can be as much as 135 µm in diameter. The soma is the site of routine cellular housekeeping functions, including the synthesis of all the neuronal proteins that are necessary for the upkeep of the axon and axon terminals (Longstaff, 2000). In common with non-neuronal cells, the soma also includes important cellular organelles, such as the nucleus, Golgi apparatus, endoplasmic reticulum (ER), ribosomes, lysosomes and mitochondria.

The nucleus

The nucleus is approximately 5–10 µm in diameter and is surrounded by a granular, double-layered membrane, known as the nuclear envelope, which is perforated by small pores measuring around 0.1 µm wide. These small pores act as passageways between the nucleoplasm (interior of the nucleus) and the surrounding cytoplasm. By comparison with non-neuronal cells, the nuclei of neurones tend to be larger, which is thought to be related to the high levels of protein synthesis within the neurone. The nucleus contains the genetic material, deoxyribonucleic acid (DNA), which is responsible for directing the metabolic activities of the cell. Messenger ribonucleic acid (mRNA) is also found within the nucleus. It is responsible for copying the specific genetic instructions from the DNA (transcription) for protein synthesis and carrying it to the site of protein production in the cytoplasm.

The rough endoplasmic reticulum (RER)

The RER is adjacent to the nucleus and is composed of rows of plate-like membranous sacs, which are covered in granular ribosomes. The RER synthesises the majority of protein needed to meet the functional demands of the neurone. It does this under the direction of mRNA. The ribosomes build proteins from amino acids delivered by transfer RNA from the genetic instructions held within messenger RNA. Rough ER is especially abundant in neurones, more so than in glia or other non-neuronal cells. It is densely packed within the soma and the shafts of dendrites, giving rise to distinct structures called Nissl bodies.

The smooth endoplasmic reticulum (SER)

The SER is made up of an extensive network of stacked membranous structures that are continuous with the nuclear membrane and RER. It is thought to be the main site of protein-folding. Smooth ER is heterogeneous in function and, depending on its location in the soma, it has important functions in several metabolic processes including protein synthesis, carbohydrate metabolism and regulation of calcium, hormones and lipids. It also serves as a temporary storage area for vesicles that transport proteins to various destinations throughout the neurone.

The Golgi apparatus

The Golgi apparatus is a highly specialised form of smooth endoplasmic reticulum that lies furthest away from the nucleus. In most neurones, the Golgi apparatus completely surrounds the nucleus and extends into the dendrites; however it does not extend into axons. It is composed of aggregated, smooth-surfaced cisternae that are perforated by circular openings to allow the two-way passage of proteins and other molecules. It is surrounded by a mixed group of smaller organelles, which includes mitochondria, lysosomes, multivesicular bodies and vacuoles. The primary function of the Golgi apparatus is to process and package large molecules, primarily proteins and lipids, that are destined for different parts of the neurone such as the axon or dendrites.

Lysosomes

Lysosomes are the principal organelles responsible for the degradation of cellular waste-products. They are membrane-bound vesicles that contain various enzymes (acid hydrolases) that catalyse the breakdown of large unwanted molecules (bacteria, toxins, etc.) within the neurone. Lysosomes are more numerous and conspicuous in injured or diseased neurones. For this reason, they are often used as biomarkers for ageing and neurodegeneration. Multivesicular bodies are derived from primary lysosomes and are made up of several tiny spherical vesicles that also contain acid hydrolases. They are small oval shaped, single membrane-bound sacs, approximately 0.5 µm in diameter and have also been noted in various forms of neurodegeneration.

Mitochondria

Mitochondria are the ‘power houses’ of cells. They are responsible for oxidative phosphorylation and cellular respiration – crucial for the function of all aerobic cells, including neurones. Measuring between 1 µm and 10 µm in length, these organelles are concentrated in the soma and the synaptic terminals, where they produce adenosine triphosphate (ATP), the cell’s energy source (Hollenbeck and Saxton, 2005). In addition to energy production, mitochondria also perform a number of other essential functions within the neurone, which include buffering cytosolic calcium levels (Gunter et al., 2004) and sequestering proteins involved in apoptosis (see Chapter 32) (Gulbins et al., 2003). The complex folding of the cristae within mitochondria provides a large surface area to harbour a number of enzymes. These enzymes, which diffuse through the mitochondrial matrix, catalyse the critical metabolic steps involved in cellular respiration. Because of the high energy demands of cellular function and protein synthesis, the number of mitochondria correlates with the neurone’s level of metabolic activity.

The cytoskeleton

The cytoskeleton provides a dynamically regulated ‘scaffolding’ that gives neurones their characteristic shape and facilitates the transport of newly synthesised proteins and organelles from one part of the neurone to another (Brown, 2001). The main components of the cytoskeleton include microfilaments, microtubules and neurofilaments.

Microfilaments

Microfilaments are particularly abundant in axons and dendrites (neurites), but they are also distributed throughout the neuronal cytoplasm. They are also abundant in the expanded tips of growing neurites, known as growth cones (Dent et al., 2003; Kiernan, 2004). They are made from a polymer called actin, a contractile protein that is most commonly associated with muscle contraction. They are composed of two intertwined chains of actin, arranged to create double helix filaments, measuring around 4–6 nm in diameter and a few hundred nanometres in length. The main role of microfilaments is the movement of cytoskeletal and membrane proteins.

Microtubules

Microtubules measure 20–24 nm in diameter and can be several hundred nanometres in length. They are made of strands of globular protein, tubulin, arranged in a helix around a hollow core, to give the microtubule its characteristic thick-walled, tube-like appearance. Microtubules play an important role in maintaining neuronal structure and they also act as tracks for the two-way transport (see: Axonal transport ) of cellular organelles.

Neurofilaments (NFs)

Neurofilaments are a type of intermediate filament (IF), seen almost exclusively in neuronal cells. Measuring about 10 nm in diameter, neurofilaments can be several micrometres long and they frequently occur in bundles (Raine, 1999). Like their IF counterparts in non-neuronal cells, they are assembled in a complex series of steps that give rise to solid, rod-like filaments. These filaments are made up of polypeptides that are coiled in a tight, spring-like configuration. They are sparsely distributed in dendrites but they are abundant in large axons, where they facilitate axonal movement and growth.

Axonal transport

Protein synthesis does not usually occur within the axon, therefore any protein requirements for the repair and upkeep of the neurone must be met by the soma. In the soma, various components (including organelles, lipids and proteins) are assembled and packaged into membranous vesicles and transported to their final cellular destination by a process known as axonal transport (axoplasmic transport). Axonal transport involves movement from the soma, towards the synapse, called anterograde transport and movement away from the axon, towards the soma, called retrograde transport.

Axonal transport can be further divided into fast and slow subtypes. Fast anterograde transport occurs at a rate of 100–400 mm/day and involves the movement of free elements including synaptic vesicles, neurotransmitters, mitochondria, and lipid and protein molecules (including receptor proteins) for insertion/repair of the plasma membrane. Slow anterograde transport on the other hand, occurs at a rate of 0.3–1 mm/day and involves the movement of soluble proteins (involved in neurotransmitter release at the synapse) and cytoskeletal elements (Snell, 2006). Both types of anterograde transport are mediated by a group of motor proteins called kinesins (Brown, 2001). Retrograde transport involves the movement of damaged membranes and organelles towards the soma, where they are eventually degraded by lysosomes (found only in the soma). It is mediated by a different kind of motor protein known as dynein.

The axon

The organelles and cellular components already discussed are not unique to neurones and may be found (with a few exceptions) in almost any cell in the body. However, the main feature that distinguishes neurones from other cells is the axon, the projection that emerges from the soma, and its associated elaborate process of dendrites. Under the microscope, it is hard to distinguish the axon from dendrites of some neurones, but in others it is easily identified on the basis of length. Whilst some neurones have no axons at all (e.g. the amacrine cell, found in the retina), most neurones have a single axon. The axons of some neurones branch to form axon collaterals, along which the impulse splits and travels to signal several cells simultaneously.

Neurones can be broadly classified according to length of their axonal processes. Golgi type I neurones contain long-projecting axonal processes, whilst Golgi type II neurones have shorter axonal processes. Another way of classifying neurones is according to their location within the central nervous system, or on the basis of their morphological appearance. Examples of specific types of neurones include Basket, Betz, Medium spiny, Purkinje, Renshaw and Pyramidal cells. Neurones may also be classified according to the number of branches that originate from the soma (Figure 1.2):

Unipolar or pseudounipolar neurones are characterised by a single neurite that emerges and branches or divides a short distance from the soma. Most sensory neurones of the peripheral nervous system are unipolar.

Bipolar neurones are characterised by a single axon and a single dendrite that emerge from opposite ends of an elongated soma. These types of neurones are found in the sensory ganglia of the cochlear and vestibular system and also in the retina.

Multipolar neurones are characterised by a number of dendrites that arise and branch close to the soma. They make up the majority of neurones in the CNS.

Figure 1.2 Structural classification of neurones. Breaks indicate that axons are longer than shown. (a) Multipolar neurone. (b) Bipolar neurone. (c) Unipolar neurone.

Reproduced from Principles of Anatomy and Physiology 12e by Gerard Tortora and Bryan Derrickson. Copyright (2009, John Wiley & Sons). Reprinted with permission of John Wiley & Sons Inc.

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The primary function of the axon is to transmit electrochemical signals to other neurones (sometimes over a considerable distance). Transmission occurs at rates that are appropriate to the type and function of the individual neurone. Because of this, the axonal length of a given neurone may vary from as little as a few micrometres, to over 1 metre in humans. For example, the sciatic nerve, which runs from the base of the spine to the foot, may extend a metre or even longer. Typical diameters can range from 0.2 to 20 µm for large myelinated axons.

The axon has four regions: the axon hillock (or trigger zone), the initial segment, the axon proper and the axon terminals. The axon hillock originates at the soma; adjacent to the axon hillock is the initial segment. The plasma membranes of these two regions contain large numbers of specialised, voltage sensitive ion channels and most action potentials originate in this area (see below: Action potentials). Beyond the initial segment, the axon proper maintains a relatively uniform, cylindrical shape, with little or no tapering. The consistent diameter of the axon (axon calibre) is maintained by components of the cytoskeleton and this feature also helps to maintain a uniform rate of conduction along the axon. In addition to the axon calibre, the rate of conduction along the axon is influenced by the presence of the myelin sheath, which begins near the axon hillock and ends short of the axon terminals.

Myelination

Myelin is a specialised protein, formed of closely apposed glial cells that wrap themselves several times around the axon (Kiernan, 2004). In the central nervous system, the glial cells making up the myelin sheath are called oligodendrocytes, whereas in the peripheral nervous system, they are known as Schwann cells (see: Neuroglia). Several axons may be surrounded simultaneously by a single glial cell.

The myelin sheath insulates the axon and prevents the passive movement of ions between the axoplasm and the extracellular compartment. Myelinated axons also contain gaps at evenly-spaced intervals along the axon, known as nodes of Ranvier (Figures 1.1 and 1.3). These nodes are the only points where the axonal membrane is in direct contact with the extracellular compartment and where ions can readily flow across the axonal membrane. Therefore, any electrical activity in the axon is confined to this part. In myelinated axons, the nodes of Ranvier contain clusters of voltage-gated sodium (Na+) channels, whereas in unmyelinated axons, these voltage-gated Na+ channels are distributed uniformly along the whole of the axon. This feature enables the axon to conduct action potentials over long distances, with high fidelity and a constant speed, and underlies the ability of the neurone to conduct impulses by a process known as saltatory conduction. Saltatory conduction (from the Latin saltare, to ‘jump’), enables action potentials to literally jump from one node to the next, rather than travelling along the membrane (Ritchie, 1984). Saltation allows significantly faster conduction (between 10 and 100 metres per second) in myelinated axons, compared with the slower conduction rates seen in their unmyelinated counterparts.

Figure 1.3 A single oligodendrocyte is capable of myelinating a single internode of numerous axons.

Reproduced from Maria A Patestas and Leslie P Gartner, A Textbook of Neuroanatomy, Wiley-Blackwell, with permission.

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The increased speed afforded by saltatory conduction therefore allows the organism to process information more quickly and to react faster, which confers a distinct advantage for survival. In addition to this, the high concentrations of ion channels at the nodal intervals conserve energy, as they reduce the requirements for sodium–potassium pumps throughout the axonal membrane. Multiple sclerosis (MS) is a demyelinating disease, characterised by patchy loss of myelin in the brain and spinal cord. As a result of the demyelinating process, plaques develop in the white matter, which result in a reduced concentration of sodium ion channels at the nodes of Ranvier and a slowing of action potentials (see Chapter 28).

The terminal portion of the axon is known as the axon terminal, where the axon arborises (or branches) and enlarges. This region goes by a variety of other names, including the terminal bouton, the synaptic knob or the axon foot. The axon terminal contains synaptic vesicles which contain neurotransmitters (see: Neurotransmitters).

Dendrites

Dendrites are the afferent components of neurones, i.e. they receive incoming information. The dendrites (together with the soma) provide the major site for synaptic contact made by the axon endings of other neurones. Dendrites are generally arranged around the soma of the neurone in a stellate (or star-shaped), configuration. In some neurones, dendrites arise from a single trunk, from which they branch out, giving rise to the notion of a dendritic tree (Raine, 1999). Under the microscope, it can be difficult to distinguish the terminal segments of axons from small dendrites, or small unmyelinated axons. However, unlike the diameters of axons, the main distinguishing feature of dendrites is that they taper, so that successive branches become narrower as they move further away from the soma. In addition, unlike axons, small branches of dendrites tend to lack any neurofilaments, although they may contain fragments of Nissl substance; however, large branches of dendrites proximal to the axon may contain small bundles of neurofilaments. The synaptic points of contact on dendrites occur either along the main stems or at small eminences known as dendritic spines – the axon terminals of other neurones adjoin these structures.

NEUROGLIA

Neuroglia (Figure 1.4), usually referred to simply as glia (from the Greek word meaning ‘glue’) or glial cells, are morphologically and functionally distinct from neurones. Neuroglia comprise almost half the total volume of the brain and spinal cord. They are smaller than neurones and more numerous – outnumbering them almost 10-fold (Snell, 2006). Although they have complex processes extending from their cell bodies, they lack any axons or dendritic processes.

Figure 1.4 Neuroglia of the central nervous system (CNS).

Reproduced from Principles of Anatomy and Physiology 12e by Gerard Tortora and Bryan Derrickson. Copyright (2009, John Wiley & Sons). Reprinted with permission of John Wiley & Sons Inc.

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Previously it was assumed that glia do not participate directly in any signalling or synaptic interactions with other neurones. However, recent studies have indicated that their supportive functions help to define synaptic contacts and that they are crucial facilitators of action potentials. Other roles attributed to neuroglia include: maintaining the ionic environment in the brain, modulating the rate of signal propagation, and having a synaptic action by controlling the uptake of neurotransmitters. They also provide a scaffold for some aspects of neural development, and play an important role in recovery from neuronal injury (or, in some instances, prevention). They also have an important nutritive role and release factors which modulate pre-synaptic function.

There are four main types of glial cells in the mature CNS: astrocytes, oligodendrocytes, microglial cells and ependymal cells – the description, location and function of these are summarised in Table 1.1.

Table 1.1 Description, location and function of specific neuroglia.

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CNS – central nervous system; PNS – peripheral nervous system; BBB – blood–brain barrier; CSF – cerebrospinal fluid.

COMMUNICATION BY NEURONES

The resting membrane potential

The neuronal membrane is about 8 nm thick and is made up of a hydrophobic lipid bi-layer, which acts as a selective barrier to the diffusion of ions between the cytoplasm (intracellular) and extracellular compartments. The unequal distribution of ions (positively or negatively charged atoms) either side of the cell membrane results in a difference of electrical charge (potential difference) between the inside and the outside of the cell membrane. The overall effect of this gives rise to the resting membrane potential. It is called the resting membrane potential because it occurs when the neurone is in an unstimulated state, i.e. not conducting an impulse. In this state, the neurone is said to be polarised, because there is a relative excess of positive electrical charge outside the cell membrane and a relative excess of negative charge inside. To maintain a steady resting membrane potential, the separation of charges across the membrane must be constant, so that any efflux of charge is balanced against any charge influx (Gilman and Winans Newman, 2003). By convention therefore, the charge outside the neuronal membrane is arbitrarily defined as zero, whilst the inside of the neurone (relative to the outside) is negatively charged (−70 mV).

The extracellular fluid contains a dilute solution of sodium (Na+) and chloride (Cl−) ions. By contrast, the axoplasm contains high concentrations of potassium (K+) ions and organic anions (large negatively charged organic acids, sulphates, amino acids and proteins) (Holmes, 1993). Two passive forces (diffusional and electrostatic) act simultaneously upon these ions to maintain the resting potential. Diffusional (chemical) forces drive Na+ ions inwards and K+ ions outwards, from areas of high concentration to areas of low concentration, i.e. down their respective chemical concentration gradients. Secondly, electrostatic forces (charge) move ions across the membrane, in a direction that depends on their electrical charge, so that the positively charged Na+ and K+ ions are attracted towards the negatively-charged cell interior (Waxman, 2000).

In addition to these diffusional and electrostatic forces, the resting potential is also influenced by the action of ion-specific membrane-spanning channels. These ion channels selectively allow the passage of certain ions, whilst excluding others. Two types of ion channels exist, which can be in an open or closed state: voltage gated and non-gated ion channels. Non-gated channels, which are primarily important in maintaining the resting potential are always open and are not influenced significantly by extrinsic factors, these gates allow for the passive diffusion of K+ and Na+ ions. Gated channels, however, open and close in response to specific electrical, mechanical, or chemical signals and their conformational states (i.e. whether they are open or not) depend on the voltage across them (Longstaff, 2000). When the neurone is polarised (i.e. is at resting membrane potential) these gates are closed.

At resting membrane potential, the neuronal membrane is relatively permeable to K+ ions, which passively diffuse out of the cell, through non-gated potassium channels. This causes a net increase in the negative charge on the inside of the cell membrane. In addition to the outward leakage of potassium, negatively charged anions (which cannot diffuse across the membrane because of their large size) add further to the overall negative intracellular charge. The majority of sodium channels are closed at resting membrane potential, so diffusion of Na+ along its own ionic gradient is prevented. In addition, the sodium–potassium pump actively transports Na+ ions out of the cell, while taking in K+. The pump moves three sodium ions out of the cell for every two potassium ions that it brings in. The sodium–potassium pump therefore moves Na+ and K+ against their net electrochemical gradients, which requires the use of energy (from the hydrolysis of ATP).

As long as the force of the K+ ions diffusing outwards exceeds the oppositely oriented electrical charge, a net efflux of K+ continues from inside the cell. But as more K+ ions travel out (along the K+ concentration gradient), the electrical force (negative charge) attracting K+ ions into the cell, gradually increases (Wright, 2004; Barnett and Larkman, 2007). If a state was reached whereby the chemical and electrical forces balanced, (equilibrium potential of potassium) there would be no K+ ion movement. This equilibrium potential for potassium occurs at −90 mV. However an equilibrium potential for potassium is never quite reached due to the small continual leakage of sodium from the cell.

Changes in the resting membrane potential

Changes in the resting membrane potential will occur when a stimulus causes gated ion channels to open thereby changing the membrane’s permeability to an ion. Depending on the type and strength of the stimulus, the change in the resting membrane potential will produce either a graded potential or an action potential. If the stimulus alters a local area of the membrane only and does not conduct far beyond the point of stimulation it is referred to as a graded potential (see below: Neurotransmitters). If the stimulus is of sufficient strength to cause a change in the entire membrane potential the response is referred to as an action potential.

An increase in the negativity of the resting membrane potential, e.g. −70 mV to −80 mV is referred to as hyperpolarisation. Conversely, any reduction in the negativity of the membrane potential, e.g. −70 mV to −65 mV, is referred to as depolarisation.

The action potential

An action potential (Figure 1.5) is initiated when a stimulus causes the voltage gated sodium channels to open. Sodium ions rapidly diffuse through the neuronal membrane down their electrochemical gradient attracted by the negative charge inside the neurone. The most common site of initiation of the action potential is the axon hillock (also called the trigger zone), where the highest concentration of voltage-gated ion channels is found (previously described).

Figure 1.5 Action potential in a neurone.

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The rush of Na+ into the neurone briefly reverses the polarity of the membrane from a negative charge of −70 mV (resting membrane potential) typically to a positive charge of +30 mV (depolarisation). The influx of Na+ and subsequent depolarisation of one section of the axonal membrane, i.e. the trigger zone, is the stimulus to open additional voltage gated sodium channels in the adjacent membrane, thus the depolarisation spreads forward along the axonal membrane. The voltage gated sodium channels are open only briefly, they become inactivated when the charge reaches +30 mV, stopping any further influx of Na+ into the neurone. This brief alteration in charge lasts approximately 5 milliseconds.

Whilst the voltage gated sodium channels are closing, voltage-gated potassium channels open resulting in a huge efflux of K+ ions (downward stroke) which continues until the cell has repolarised to its resting potential (from +30 mV to −70 mV). During repolarisation the voltage gated sodium channels remain inactivated.

Following repolarisation, the neurone is briefly unyielding to any further action potentials, a phase known as the recovery/relative refractory period. The absolute refractory period is the time during which a second action potential absolutely cannot be initiated (see Figure 1.5). The sodium–potassium pump actively transports K+ and Na+ ions across the membrane, (against their respective chemical concentration gradients), to re-establish the resting potential.

Threshold stimulus and the all-or-none phenomenon

The stimulus must depolarise the membrane potential to a threshold value, which is typically to −55 mV for an action potential to occur. If the membrane does not reach the threshold value an action potential will not occur. If the threshold is reached the action potential will propagate forward at maximal strength regardless of the strength of the initial stimulus. Therefore the action potential will occur maximally or not at all. This is the ‘all-or-none phenomenon’.

NEUROTRANSMISSION

Synapses

Once the action potential reaches the axon terminal it needs to transfer to another cell. The synapse (Figure 1.6) is the location of signal transmission from one neurone to another or, in most cases, many other neurones. The synapse is typically between the axon terminal of a neurone (pre-synaptic) and the surface of a dendrite or cell body of another neurone (post-synaptic). The number of synaptic inputs to a typical neurone in the human nervous system ranges from 1 to about 100,000, with an average in the thousands.

Figure 1.6 An example of an ionotropic effect occurring at a synapse indicating the events that occur before, during, and after the release of neurotransmitter substances.

Reproduced from Maria A Patestas and Leslie P Gartner, A Textbook of Neuroanatomy, Wiley-Blackwell, with permission.

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Two types of synapse exist: electrical and chemical. In electrical synapses, ion channels (connections) arrange themselves around a central hollow core to form gap junctions. These gap junctions allow electrical coupling and the passage of water, small molecules (<1.2 nm diameter) and various ions between adjacent cells. Electrical synapses are predominantly associated with electrical activity in cardiac and smooth muscle. They are also found between astrocytes and are crucially involved in the coupling of horizontal cells found in the retina. Electrical signalling is bi-directional in electrical synapses.

In humans, the majority of synapses are chemical synapses and therefore rely on the release of neurotransmitters and their binding with receptor proteins on the post-synaptic membrane of the target neurone. Typically, the pre-synaptic terminal is immediately adjacent to a post-synaptic region but there is no physical continuity between these regions. Instead, the components communicate by chemical neurotransmitters that cross the extracellular space known as the synaptic cleft to bind to receptors in the post-synaptic region.

Neurotransmitters

Neurotransmitters are the molecules responsible for chemical signalling in the nervous system. Neurotransmitters are synthesised in the soma and are transported to the terminal parts of the axon (near the synaptic region), where they are packaged into vesicles and stored in areas known as active zones, ready for release at the synapse. When an action potential reaches the axon terminal voltage gated calcium channels open, the influx of calcium ions cause the vesicles to fuse with the pre-synaptic membrane and vesicular contents are released in discreet packets or quanta, into the synaptic cleft, by a process of exocytosis. Each quantum represents the release of the contents of a single vesicle (around 4000 molecules of neurotransmitter) (Longstaff, 2000). Following exocytosis, the vesicular membrane proteins are recycled by a process known as endocytosis .

The first neurotransmitter to be described was acetylcholine (ACh), by Loewi in 1926, following his extensive work on frog cardiac muscle. Subsequently, a wide range of other neurotransmitters have been described, each of which may be chemically differentiated on the basis their molecular structure, patterns of distribution, localisation to specific brain areas and their association with specific functions (Michael-Titus et al., 2007).

The effects of the main neurotransmitters and their mode of action are summarised in Table 1.2.

Table 1.2 Key central nervous system neurotransmitters.

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In addition to the principal neurotransmitters, other chemicals can also modulate the impact of neurotransmitter on the post-synaptic neurone. They do this by enhancing, prolonging, inhibiting or limiting the effect of a particular neurotransmitter on the post-synaptic neurone, so that the response of metabotropic receptors (see below) may last several minutes or longer. These substances are called neuromodulators, because they modulate the response of the neurone to other inputs. It is widely accepted that some molecules can act simultaneously as a neurotransmitter or a neuromodulator (termed co-transmission) and classification largely depends on whether its action occurs over a long range or is localised to the synapse.

Neurotransmitters exert their effects on post-synaptic receptors of target neurones. The action of a given neurotransmitter on a target neurone or indeed peripherally on a particular effector organ (see Chapter 5) largely depends on the types of receptors present on that target. Most types of neurotransmitters have a number of specific receptor subtypes that they can activate. These receptors can be classified according to their overall structure and function. The effects of neurotransmitters depend on the summation of responses at the post-synaptic membrane.

Two broad superfamilies of receptor have been described, which include ionotropic and metabotropic receptors. The ionotropic, or ligand-gated ion channel receptors, are made up of ion-selective channels that are integral to the receptor. Binding of neurotransmitter directly results in the selective opening or closure of the channel and directly increasing or decreasing its permeability to particular ions, as described above.

Ionotropic or ligand-gated ion channel receptors

The binding of a neurotransmitter to an ionotropic receptor will cause a change in the post-synaptic membrane potential by either bringing about the opening or closing of ion channels. When the neurotransmitter causes the opening of positive ion channels (e.g. Na+ channels) in the post-synaptic membrane the net effect is to reduce the negativity of the membrane potential (e.g. from −70 mV to −68 mV). This is known as an excitatory post-synaptic potential (EPSP). This is below the level required to lift the potential to threshold level for an action potential to occur. When the neurotransmitter causes the opening of potassium channels, thereby allowing positive ions to leave the neurone, or opens chloride (Cl−) channels the effect is to reduce the resting potential i.e. make it more negative this is known as inhibitory post-synaptic potential (IPSP). The IPSP reduces the post-synaptic neurone’s ability to generate an action potential. These small shifts are called graded potentials. Whether an action potential is generated or not depends on the summation of the graded potentials. Several EPSPs are needed to convert resting potential to an action potential. Summation may be temporal (the cumulative effect of repeated impulses from a single synapse) or spatial (the net effect of simultaneous impulses from different synapses along the membrane).

The second superfamily of receptors are known as the metabotropic receptors. Binding of neurotransmitters to these receptors has longer lasting effects on the post-synaptic cell. When a neurotransmitter binds to these receptors, small intracellular proteins called G-proteins are activated. G-proteins exert their effects on the post-synaptic membrane by binding ion channels directly, or by indirectly activating second messengers. Second messengers are molecules that are produced or released inside the cell; the most common being cyclic-adenosine monophosphate (cAMP). Second messengers can activate other enzymes in the cytosol that can regulate ion-channel function or alter the metabolic activities of the cell, hence the name metabotropic.

Inactivation and removal of neurotransmitters

Typically, neurotransmitter binding takes less than 5 µs, but not all neurotransmitter that has been released binds to the post-synaptic membrane of the target neurone. The distance between the pre- and post-synaptic membrane is as little as 12 nm across, but due to reuptake of neurotransmitter, passive diffusion away from the synaptic cleft and inactivation by various enzymes, the amount of transmitter available for binding is reduced. For example, enzymatic degradation of ACh (by acetylcholinesterases) takes place in the synaptic cleft at the neuromuscular junction or other cholinergic synapses. These enzymes cleave ACh into its inactive components, acetate and choline, which are recycled and used to synthesise further ACh by combination with acetyl-coenzyme-A.

Other neurotransmitters are inactivated in a similar way, or they may be inactivated by direct removal from the synaptic cleft. Direct removal from the synaptic cleft is carried out by reuptake transporters, which actively transport unused neurotransmitter to surrounding neurones or glia. The importance of the mechanisms of reuptake is highlighted by the impact of certain drugs on brain function. Illicit drugs, such as ecstasy (3, 4-methylenedioxy-N-methamphetamine; MDMA), for example, block the reuptake of serotonin (5-hydroxytryptamine; 5HT). This results in an excess of serotonin in the synaptic cleft, which contributes to its euphoric effects (McCann et al., 2005). Similarly, other illicit drugs such as cocaine inhibit the reuptake of dopamine, which is responsible for its euphoric and addictive effects (Mash et al., 2002). Of course, neurotransmitter reuptake blockade can also have more useful, therapeutic applications, for example in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs), which block the reuptake of serotonin. The therapeutic use of drugs that inhibit reuptake of neurotransmitters will be discussed in the relevant chapters on specific diseases.

SUMMARY

The nervous system is vital for maintaining the homeostasis of the body. It continuously receives information which it must process and rapidly respond to. These vital functions are made possible by the generation of action potentials and chemical synapses. Neurotransmitters released at a synapse can have either excitatory or inhibitory effects whereas neuromodulators prolong, inhibit, or limit the effect of a particular neurotransmitter on the post-synaptic neurone.

REFERENCES

Barnett MW, Larkman PM (2007) The action potential. Practical Neurology 7(3): 192–197.

Brown AG (2001) Introduction to nerve cells and nervous systems. In: Nerve Cells and Nervous Systems: an introduction to neuroscience. (2nd edition). London and New York: Springer.

Dent EW, Tang F, Kalil K (2003) Axon guidance by growth cones and branches: common cytoskeletal and signaling mechanisms. Neuroscientist 9(5):343–353.

Gilman S, Winans Newman S (2003) Physiology of nerve cells. In Manter and Gatz’s Essentials of Clinical Neuroanatomy and Neurophysiology. (10th edition). John Tinkham Manter, Arthur John Gatz, Sarah Winans Newman eds. Philadelphia: FA Davis.

Gulbins E, Dreschers S, Bock J (2003) Role of mitochondria in apoptosis. Experimental Physiology 88(1):85–90.

Gunter TE, Yule D I, Gunter KK et al. (2004) Calcium and mitochondria. FEBS Letters 567(1):96–102.

Hollenbeck PJ, Saxton WM (2005) The axonal transport of mitochondria. Journal of Cell Science 118(23):5411–5419.

Holmes O (1993) Nerve. (2nd edition). London, Chapman and Hall.

Kiernan JA (2004) Barr’s The Human Nervous System: an anatomical viewpoint. Baltimore: Lippincott Williams and Wilkins.

Longstaff A (2000) Neuroscience. Oxford, BIOS Scientific Publishers Limited.

Mash DC, Pablo J, Ouyang Q (2002) Dopamine transport function is elevated in cocaine users. Journal of Neurochemistry 81(2):292–300

McCann UD, Szabo Z, Seckin E et al. (2005) Quantitative PET studies of the serotonin transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB. Neuropsychopharmacology 30(9):1741–1750.

Michael-Titus A, Revest P, Shortland P (2007) Elements of cellular and molecular neuroscience. In: Michael-Titus A, Revest P, Shortland P (eds). Nervous System. Edinburgh: hurchill Livingstone.

Raine CS (1999) Neurocellular anatomy. In Basic Neurochemistry: Molecular, cellular and medical aspects. (6th edition). George J. Siegel et al. eds. Philadelphia: Lippincott-Raven Publishers.

Ritchie JM (1984) Physiological basis of conduction in myelinated nerve fibres. In: Myelin. Pierre Morell ed. New York: Plenum Press pp 117–146.

Snell R (2006) The neurobiology of the neuron and the neuroglia. In: Clinical Neuroanatomy. (6th edition). Baltimore: Lippincott, Williams and Wilkins pp 31–67.

Waxman SG (2000) Signaling in the nervous system In: Correlative Neuroanatomy. (24th edition). John Butler and Harriet Lebowitz eds. New York: McGraw-Hill pp 20–34.

Wright SH (2004) Generation of resting membrane potential. Advances in Physiology Education 28(1–4):139–142.

2

The Structural and Biochemical Defences of the CNS

Ehsan Khan

INTRODUCTION

The central nervous system (CNS) is one of the most delicate structures within the body. It is a vital part of the body that needs to function continuously to maintain life. The tissue that comprises the CNS is extremely delicate, and the CNS is consequently extremely susceptible to both mechanical and chemical insult. To reduce the risk of mechano-chemical injury, protection of this delicate system comprises structural as well as biochemical defences. This chapter will describe the defensive features of the CNS, providing the reader with a conceptual and functional understanding of these structures and processes. This information will help the reader to understand the clinical consequences of failure of these structures and processes.

The defences of the central nervous system include the following.

Structural defences:

Bony encasement

Membranes – meninges and the blood–brain barrier (BBB)

Cerebrospinal fluid (CSF)

Biochemical defences:

Enzymes

Efflux proteins

Metabolic enzymes

BONY ENCASEMENT

The skull

The skull is made up of a number of flat bones that are joined together by serrated junctions known as sutures (Figure 2.1). The skull comprises the cranial and facial bones. The cranial bones include the brain casing or the skull cap (the calvaria) and the bones of the cranial cavity floor. The sinusoidal flat bones of the skull have a spongy diploe centre that is sandwiched between the hard external and internal compact layers of the skull bone. This arrangement affords the skull considerable strength and resistance to trauma while maintaining a low weight. It provides protection together with support and ease of movement of the head.

Figure 2.1 Medial view of sagittal section of skull. Although the hyoid bone is not part of the skull, it is included in the illustration for reference.

Reproduced from Principles of Anatomy and Physiology 12e by Gerard Tortora and Bryan Derrickson. Copyright (2009, John Wiley & Sons). Reprinted with permission of John Wiley & Sons Inc.

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The calvaria

The skull cap or calvaria is formed by the frontal bone, two parietal bones and the occipital bone.

The fontal bone

The frontal bone is the anterior segment of the calvaria which joins with the anterior two halves of the parietal bones by the coronal suture. The frontal bone can be divided into the flat anterior section the squamous frontalis (forehead) and the horizontal inferior portion (pars orbitalis) that forms the superior borders of the orbits and nasal cavity.

Internally the frontal bone has a longitudinal protuberance that runs anterior–posteriorly. The initial portion of this protuberance is known as the frontal crest and gives rise to a swollen rough surface (the crista galli) which serves as a point of attachment for the falx cerebri, the fold of dura matter that sagittally divides the two cerebral hemispheres. The frontal crest travels posteriorly forming a shallow groove the sagittal sulcus which houses the superior sagittal sinus.

The parietal bones

The parietal bones make up the lateral surfaces and superior surface of the calvaria and are joined by the sagittal suture. The parietal bones join inferiorly with the temporal bone by the squamous suture and posteriorly to the occipital bone by the lambdoid suture. Internally there are bilateral grooves for the middle meningeal arteries and a larger groove, the sagittal sulcus that extends from the frontal bone and houses the superior sagittal sinus.

The occipital bone

The occipital bones form the posterior surface of the calvaria covering the occipital lobes of the brain. The occipital bone is trapezoid in shape and curved to form the posterior and posterior-inferior wall (squamous occipitalis) of the cranial cavity floor. It joins the two temporal bones by the occipito-mastoid sutures. There is a large opening in the inferior part of the bone called the foramen magnum, which provides a passage for the spinal cord from the cranium into the vertebral column.

Internally the occipital crest provides posterior attachment for the falx cerebri. There is a bilateral groove for the posterior meningeal arteries. There is a sloping depression above the anterior margin of the foramen magnum known as the clivus which provides space for the pons. Towards the anterior portion of the foramen magnum is a small opening, the hypoglossal canal, which as its names suggests provides passage for the XII cranial nerve (hypoglossal) to the tongue.

Floor of the cranial cavity

The floor of the cranial cavity is formed by the temporal, sphenoid and ethmoid bones.

Temporal bones

Below the parietal bone is the temporal bone. Due to its association with many other structures, i.e. the ears, pharynx and cranial nerves, it has a complex structure and comprises five parts:

Squamous

Mastoid

Petrous

Tympanic

Styloid process

The squamous part of the temporal bone

This bone forms a border superiorly with the parietal bone via the squamousal suture. Externally the squamous bone provides attachment for the temporal muscle and fascia via a marked line, the temporal line. Continuing from this line is a thick process that projects from the inferior part of the temporal bone called the zygomatic process which forms the beginnings of the cheek bone. Internally there is a groove for the middle meningeal arteries.

The mastoid portion of the temporal bone

This bone has a number of borders. Posteriorly it joins with the occipital bone via the occipitomastoid suture and the parietal bone via the parietomastoid suture. Superiorly it is continuous with the squamous part of the temporal bones. Anteriorly the mastoid contributes to the formation of the external auditory meatus and the auditory cavity. The mastoid process provides attachment to the large sternocliedomastoid muscle. Internally the mastoid presents a deep groove, the sigmoid sulcus that supports the transverse sinus. The sigmoid sulcus has an opening, the mastoid foramen, that provides passage for blood vessels to the transverse sinus and occipital dura mater.

The petrous part of the temporal bone

This bone is located anterior to the mastoid process, and inferior and medial to the temporal line, which it joins via the petrosquamous suture, forming and housing structures essential for hearing. It is an extremely dense and hard bone.

The tympanic part of the temporal bone

This bone is found lateral to the petrous part, inferio-posterior to the squamous part and anterior to the mastoid part of the temporal bone. This part of the temporal bone surrounds the external auditory meatus (external ear canal).

The styloid process of the temporal bone

The styloid process serves as attachment for several tongue and neck muscles.

Sphenoid bone

The sphenoid bone is located in the middle of the base of the skull (Figure 2.2). The sphenoid bone is made up of a cuboidal central portion from which two bony plates radiate on each side. Together these structures provide surfaces for particular brain structures and openings for a number of cranial nerves and blood vessels.

Figure 2.2 Sphenoid bone. (a) Superior view of the sphenoid bone in floor of cranium. (b) Anterior view of sphenoid bone.

Reproduced from Principles of Anatomy and Physiology 12e by Gerard Tortora and Bryan Derrickson. Copyright (2009, John Wiley & Sons). Reprinted with permission of John Wiley & Sons Inc.

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The superior surface of the main body of the sphenoid bone is divided sagittally by the ethmoid spine that articulates with the cribriform plate of the ethmoid bone, behind which on either side is an area for the olfactory bulbs. Posterior to this is a groove, the pre-chiasmatic groove, which terminates bilaterally with the optic foramen that allows the optic nerve and ophthalmic artery to enter the orbital cavity. The pre-chiasmatic groove is bordered posteriorly by a ridge, the tuberculum sellae, which continues into a deep depression, the sella turcica. The deepest part of this, the hypophyseal fossa, provides space for the pituitary gland.

Posterior to the hypophyseal fossa is a bony plate known as the dorsum sallae, which has small processes on either side to attach the tentorium cerebri, a sheet of dura mater that separates the cerebellum from the occipital lobes.

Running laterally either side the body of the sphenoid bone is a series of openings. On the level of the hypophyseal fossa is a bilateral fissure, the superior orbital fissure, that divides the two radiating plates of the sphenoid bone into the anterior lesser wings and posterior greater wings. This fissure is of great importance as it acts as a passage for a number of structures including the oculomotor [III], trochlear [IV], ophthalmic branch of the trigeminal nerve [V], and abducen [VI] nerves, and the ophthalamic veins.

Posteriorly and towards the medial aspect of the superior orbital fissure is a large opening, the foramen rotundum, that provides passage for the maxilliary nerve. Posterior-lateral to the foramen rotundum is the foramen ovale. The mandibular nerve, accessory meningeal artery, the lesser superficial petrosal artery and the emissary veins pass through this large opening.

Finally, on the border of the spheno-occipital junction, posterior-lateral to the foramen ovale is a smaller opening, the foramen spinosum. This opening may be absent or combined with the foramen ovale. It normally allows passage of the middle meningeal artery and a branch of the mandibular nerve, the spinous nerve, which divides into an anterior and posterior branch to innervate the dura mater.

The ethmoid bone

The ethmoid bone separates the nasal cavity from the cranial cavity. It has a complex shape. It forms most of the bony area between the nasal cavity and the orbits. It consists of the cribriform plate, that forms part of the anterior-basal floor of the cranial cavity. The perpendicular plate, which forms the bony part of the nasal septum and two lateral masses of bone the ethmoidal labyrinths.

The cranial cavity

In clinical practice reference is often made to the three cranial fossae that make up the cranial cavity. These are the:

Anterior cranial fossa which accommodates the frontal lobes of the brain

Middle cranial fossa which accommodates the two temporal lobes

Posterior cranial fossa which houses the cerebellum and the brain stem

The vertebral column

The vertebral column (Figure 2.3) encompasses and protects the spinal cord. It also supports a number of muscles and provides fixation for ligaments as well as articular surfaces for bones of the lower limbs. Owing to this varied function the bones of the vertebral column, although similar in structure, vary in terms of projections and attachment surfaces.

Figure 2.3 Vertebral column. The numbers in parentheses in (a) indicate the number of vertebrae in each region. (a) Anterior view showing regions of the vertebral column. (b) Right lateral view showing four normal curves.

Reproduced from Principles of Anatomy and Physiology 12e by Gerard Tortora and Bryan Derrickson. Copyright (2009, John Wiley & Sons). Reprinted with permission of John Wiley & Sons Inc.

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The vertebral column consists of 26 segments or vertebrae divided into five different regions:

Cervical (C1–C7)

Thoracic (T1–T12)

Lumbar (L1– L5)

Sacral (S1–S5, fused)

Coccygeal (Co1–Co4, fused)

A vertebra

A typical vertebra (Figure 2.4) has two main parts. The anterior portion is centrally formed from spongy cancellous bone and surrounded by a hard external shell, the cortical rim. This part of the vertebra is known as the body or centrum and is the weight bearing region. This bone formation is clearly defined in all but the first two cervical vertebrae. Arising posteriorly from either side of the body are short bony processes called the pedicles which join with flattened plates of bone called the laminae.

Figure 2.4 Structure of a typical vertebra, as illustrated by a thoracic vertebra. In (b) only one spinal nerve has been included, and it has been extended beyond the intervertebral foramen for clarity. The sympathetic chain is part of the autonomic nervous system. (a) Superior view. (b) Right posterolateral view of articulated vertebrae.

Reproduced from Principles of Anatomy and Physiology 12e by Gerard Tortora and Bryan Derrickson. Copyright (2009, John Wiley & Sons). Reprinted with permission of John Wiley & Sons Inc.

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Together these four bones form the vertebral (neural) arch, which provides space for the spinal cord and is known as the vertebral canal (foramen). This is the second feature shared by most vertebrae. Dorsal to the neural arch a hard spine of bone, the spinous process, is found. This structure provides attachment to different muscles and ligaments. It is poorly defined in the first cervical vertebra. Laterally on either side of the vertebra arising from the border of the body and neural arch is a further bony process known as the transverse process. These processes, like the spinous process, attach different muscles and ligaments. In addition each vertebra has 4 smaller articular processes, two superior and two inferior. These processes correspond with articular surfaces on opposing vertebrae to provide torsional strength and a degree of flexibility to the vertebral column.

Cervical vertebrae

The first cervical vertebra is known as the atlas and joins the vertebral column to the skull together with the second cervical vertebra, the axis. The atlas is devoid of a body and spinous process but has short and strong transverse processes that contain an opening, the transverse foramen, which provides passage for the vertebral artery and vein and the nerves of the sympathetic nervous system (Figure 2.5a). The second cervical vertebra, the axis, differs from the atlas in that it has a clearly defined and prominent body that projects upwards called the odontoid peg (Figure 2.5b). Together the atlas and axis allow pivotal motion of the skull. The remainder of the cervical vertebrae have a clearly defined body and spinous process with short transverse processes.

Figure 2.5 Cervical vertebrae. (a) Superior view of atlas (C1). (b) Superior view of axis (C2).

Reproduced from Principles of Anatomy and Physiology 12e by Gerard Tortora and Bryan Derrickson. Copyright (2009, John Wiley & Sons). Reprinted with permission of John Wiley & Sons Inc.

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Thoracic vertebrae

The 12 thoracic vertebrae have a ‘typical’ vertebral shape with a well developed body, spinous and transverse processes. The thoracic vertebrae, except for the 11th and 12th, have two additional articular surfaces for each rib.

Lumbar vertebrae

The lumbar vertebrae have a well developed body with short spinous and transverse processes. The lumbar vertebrae possess the most well developed bodies of all the vertebrae as they are the main weight bearing vertebrae. Despite this robust structure they are the vertebrae that are most commonly associated with lower back pain.

The sacrum

The sacrum is made up of five fused bones, which have strong and broad lateral processes. The bodies of the vertebrae become progressively compressed dorso-ventrally to give rise to a broad flat structure that is curved ventrally. The sacrum joins with the lumbar vertebrae superiorly, the coccyx inferiorly and to the ilium of the pelvic girdle via an articular surface and strong posterior sacroiliac ligaments. The structure of the sacrum differs between male and female. The female sacrum is broader and shorter with a more acute curvature beginning half way down the structure, whereas the male sacrum has a more evenly distributed curvature.

The coccyx

The coccyx consists of four vertebrae. Although fused, these bones show a degree of movement.

THE MENINGES AND CEREBROSPINAL FLUID (CSF)

The meninges are made up of three layers of connective tissue. From the skull inwards, they are dura mater, arachnoid mater and pia mater (Figure 2.6). The protective arrangement of these membranes is akin to the protection provided by other fibrous encasements in the body like the lung pleura and foetal amniotic sac. The inner and outer membranes (dura and pia mater) impart structural support and provide a role in reducing friction between the delicate brain tissue and the internal surface of the cranium. The arachnoid mater is bathed in cerebrospinal fluid (CSF). In addition to reducing friction, the CSF provides a buoyancy to the CNS tissue, akin to amniotic fluid providing buoyancy to a foetus in the womb (Kothari and Goel, 2006). Thus together the meninges provide structural support and buoyancy to the CNS protecting it from the continuous knocks and bumps it would otherwise experience in everyday life.

Figure 2.6 Diagram of a frontal section of the skull and brain to display the three meninges: the dura mater, arachnoid, and pia mater.

Reproduced from Maria A Patestas and Leslie P Gartner, A Textbook of Neuroanatomy, Wiley-Blackwell, with permission.

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The choroid plexus

Cerebrospinal fluid is produced in the brain by modified ependymal cells in the choroid plexus. The choroid plexus (CP) constitutes a number of thin leafy structures found floating within but attached to some surfaces of the brain ventricles (Redzic and Segal, 2004). These surfaces include the floor and lateral aspects of the lateral ventricle and the roof of the third ventricle and fourth ventricles.

Production of CSF

The choroid plexus produces between 400 and 500 ml of CSF a day, however the distribution volume for CSF is only 150–175 ml. This leads to a pressure build-up that exceeds venous pressure in the brain and allows CSF to be absorbed in the arachnoid villi (see Chapter 6 for further detail). CSF is a clear and odourless, normally sterile fluid. Its main constituents and characteristics are listed below:

Specific gravity: 1.006–1.009

Glucose: 40–80 mg/dl

Total protein: 15–45 mg/dl

Lactate: less than 35 mg/dl

Leukocytes (white blood cells): 0–5/µl (adults and children); up to 30/µl (newborns)

Differential: 60–80% lymphocytes; up to 30% monocytes and macrophages; other cells 2% or less. Monocytes and macrophages are somewhat higher in neonates

Red blood cell count: Nil

CSF circulation

The CSF circulates from the lateral ventricles through the foramen of Monro into the third ventricle, and then through the cerebral aqueduct into the fourth ventricle (Figures 2.7, 2.8), where it exits through two lateral apertures (foramina of Luschka) and one median aperture (foramen of Magendie). It then flows through the cerebromedullary cistern down the spinal cord and over the cerebral hemispheres. From there the CSF is absorbed via the arachnoid villi.

Figure 2.7 Locations of ventricles within a ‘transparent’ brain. One interventricular foramen on each side connects a lateral ventricle to the third ventricle, and the aqueduct of the midbrain connects the third ventricle to the fourth ventricle. Right lateral view of brain.

Reproduced from Principles of Anatomy and Physiology 12e by Gerard Tortora and Bryan Derrickson. Copyright (2009, John Wiley & Sons). Reprinted with permission of John Wiley & Sons Inc.

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Figure 2.8 Hemisected skull demonstrating the flow of cerebrospinal fluid in the ventricles of the brain and in the subarachnoid spaces.

Reproduced from Maria A Patestas and Leslie P Gartner, A Textbook of Neuroanatomy, Wiley-Blackwell, with permission.

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Arachnoid villi

These structures are protrusions of the arachnoid mater into the subarachnoid space (Figure 2.8). In addition to these primary draining routes, Johnston et al. (2007) suggest that CSF may drain via a number of other unconventional pathways including the cavernous sinus, the adventitia of the internal carotid arteries and in lymphatic vessels emerging from the epineurium of the nerve.

Protective functions of the CSF

The unidirectional flow of CSF provides an ablutionary effect which continually removes waste and other potentially noxious substances like drugs and their metabolites from the brain (see below: CSF flow and substance clearance). The CSF provides a fluid buffer that cushions the brain against impact. Fluid buffers are particularly effective in reducing injury from impact as they decelerate the object gradually as the fluid gets compressed. The CSF lubricates the meninges to provide support and frictionless movements of the brain. Although the brain’s specific gravity is higher than CSF, 1.0329 ± 0.0014 g/ml, (Lescot et al., 2005) vs 1.006–1.009 g/ml respectively, the presence of CSF provides the brain with some buoyancy reducing pressure at the base of the brain.

Circumventricular organs (CVOs)

Circumventricular organs (CVOs) include a number of structures found at and around the ventricles in the brain. In mammals, nine organs are recognised as CVOs, the most common being: pineal gland (PIN), posterior pituitary (PP), area postrema (AP) and choroid plexus (CP).

Although part of the central nervous system, they are devoid of a typical tight blood–brain barrier (BBB) and appear to function as chemical sampling areas involved in homeostasis (the area postrema acts as a chemoreceptor trigger centre for vomiting, for example). The CVO organs are associated with a well developed and permeable capillary network. Owing to this ease of communication between the blood and brain in these areas, the CVOs are called windows of the brain (Joly et al., 2007). The functions of particular CVOs differ, however the majority provide a secretory function as well as many having a sensory function.

CSF flow and substance clearance

The large fluid flow through the ventricles acts as a convection current