Keywords

3.1 Introduction

The human nervous system mediates a wide range of functions essential for survival and well-being. The approximately 1011 neurons in the human brain offer limitless potential for the creation of complex neuronal circuits and inter-connectivity.

Neurophysiology refers to the study of neurons, and their various arrangements into nerves and nervous systems, describing their functions and the mechanisms by which they achieve these functions. When this is restricted to the brain and its various structures in the central nervous system (CNS), it may be termed central neurophysiology. A clear understanding of central neurophysiology is relevant to better appreciate the variety of pathophysiological states, including subarachnoid haemorrhage, that affect the brain.

3.2 Electrophysiology

A neuron is a specialised cell with two fundamental properties that define its functioning and importance, namely excitability and conductivity. Excitability of a neuron refers to its ability to respond to changes in or stimuli from the environment; conductivity is the ability to transmit or convey an impulse, action potential or state of excitation from one part of the cell to another. This section addresses the basic principles of neuro-electrophysiology.

3.2.1 Neuron Structure

Neuronal signals are transmitted as electrical signals by a vast network of neurons in the central and peripheral nervous system. Fibre-like processes called dendrites receive and transmit signals to the cell body, where proteins are synthesised in the basophilic granules (Nissl substances) of the rough endoplasmic reticulum. A fibre-like structure called an axon, leaves the cell body and consists of axoplasm filled with mitochondria, microtubules, neurofilaments and smooth endoplasmic reticulum. The axon ends in a nerve terminal, where neurotransmitters are released to bind with receptors on target tissue (Fig. 3.1) [2]. An axon may or may not be surrounded by a myelin sheath. Myelin sheaths consist of Schwann cells that surround the axon and slow the conduction of electrical signals by reducing ion transfer through the axonal membrane (Fig. 3.2). The junction between two adjacent Schwann cells is interrupted by a node of Ranvier, a small uninsulated area consisting of closely packed sodium channels, allowing for fast passage of ions. Electrical action potentials are able to jump between these nodes, referred to as saltatory conduction, resulting in increased velocity of nerve signal transmission with limited energy expenditure.

Fig. 3.1
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Basic anatomy of a neuron (From OpenStax College [1]—Creative Commons Attribution 4.0 International License)

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Fig. 3.2
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Anatomy of a myelinated nerve fibre with nodes of Ranvier (From OpenStax College [3]—Creative Commons Attribution 4.0 International License)

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3.2.2 The Resting Membrane Potential

During the resting state, the electrical difference across a selectively permeable membrane is determined by the difference in ion concentrations on either sides of the membrane. This is called the resting membrane potential and in nervous system cells is determined by the relatively higher intracellular concentration of K+ ions compared to the relatively higher extracellular concentration of Na+ ions. The resting membrane potential is maintained by the active Na+/K+/ATPase transport mechanism that is present in all cells of the human body. A net deficit of positive ions inside the cell is maintained by the continual pumping of three sodium ions outwards in exchange for two potassium ions inward, and creates the negative resting membrane potential of about −90 mV. This sets up large concentration gradients across the resting cell membrane, ready for activation of an action potential.

3.2.3 Depolarisation

Any stimuli, including mechanical, chemical, or electrical stimuli, that can cause a rapid change in the membrane potential by influencing permeability of the sodium and potassium ion channels, can generate electrochemical impulses necessary to transmit nerve signals. Each action potential begins with depolarisation, creating a change from the negative membrane potential to a more positive potential. An action potential will only develop if a threshold potential of between −70 and −50 mV is reached, at which point a conformational change of the voltage-gated sodium channels occur, activating the voltage-gated channel to an open state. Sodium ions stream into the cell at a high rate, causing the opening of more sodium channels (Fig. 3.3). The membrane potential quickly depolarises to about +30 mV. The inactivation gate of the sodium channel is activated at the same time but the conformational change is slower, allowing the passage of sodium ions before closing (Fig. 3.4). No further passage of sodium ions is allowed and opening of the inactivation gate will not occur until the resting membrane potential is reached, thereby avoiding any further action potentials until repolarisation is complete, also called the refractory period.

Fig. 3.3
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Voltage-gated sodium channels showing successive activation and inactivation during an action potential (From OpenStax College [3]—Creative Commons Attribution 4.0 International License)

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Fig. 3.4
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Typical voltage changes during an action potential. The formation of an action potential can be divided into five steps: (1) A stimulus from a sensory cell or another neuron causes the target cell to depolarise toward the threshold potential. (2) If the threshold of excitation is reached, all Na+ channels open and the membrane depolarises. (3) At the peak action potential, K+ channels open and K+ begins to leave the cell. At the same time, Na+ channels close. (4) The membrane becomes hyperpolarised as K+ ions continue to leave the cell. The hyperpolarised membrane is in a refractory period and cannot fire. (5) The K+ channels close and the Na+/K+ transporter restores the resting potential. (From OpenStax College [3]—Creative Commons Attribution 4.0 International License)

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3.2.4 Repolarisation

When the membrane potential increases toward 0 mV, a conformational opening of the potassium channels occur just as the sodium channels start to close. This allows the rapid movement of potassium ions out of the cell, rapidly restoring the membrane potential back to −90 mV. At this point the potassium channels return to their resting closed state. The active Na+/K+ ATPase channel is responsible for re-establishing the sodium and potassium ion gradients of the resting state, ready for the next action potential.

3.2.5 Nerve Impulse

Propagation of the action potential occurs as the depolarisation process spreads along the nerve fibre, exciting the adjacent membrane. This occurs in one direction only, spreading along the entire length of the fibre, and is called the nerve impulse. The velocity of the nerve impulse is increased in myelinated fibres and is also accelerated in axons of larger diameter.

3.2.6 Synaptic Transmission

The connection between a nerve terminal and other nerves, muscles or glands, is called a synapse, and permits the transmission of a neural impulse from one nerve to another. Transmission in mammals occur via chemical neurotransmission. Impulses can be received from several nerves (convergence) or may be transmitted via synaptic contact with many other neurons (divergence) The action potential is propagated along the axon, reaching the nerve terminal to open voltage-gated calcium channels which release neurotransmitter from vesicles into the synaptic cleft via a process called exocytosis. Thereafter, the neurotransmitters diffuse across the cleft to bind to receptors on the post-synaptic cleft either opening ion channels or activating a second messenger system (Fig. 3.5). Neurotransmitter activity in the synaptic cleft is terminated by enzymatic breakdown, reuptake into the presynaptic membrane or diffusion away from the site. If the opening of ion channels resulted in depolarisation reaching the threshold potential, the action potential is further transmitted along the new nerve.

Fig. 3.5
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A representation of a synapse showing release of neurotransmitters into the synaptic cleft and activation of post-synaptic receptors. (From OpenStax College [3]—Creative Commons Attribution 4.0 International License)

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3.3 Cerebral Metabolism

A description of cerebral metabolism under normal conditions allows for a better understanding of metabolic responses to pathological states. This section reviews the basic principles of cerebral metabolism.

The brain is one of the most metabolically active of all organs in the body. The regulation of cellular energy metabolism and metabolic supply is essential to the highly dynamic energy consumption of the CNS that is needed for cellular function and generation of electrophysiological signals. Increased neuronal activity requires adequate delivery of oxygen and nutrients to meet the increased consumption of energy. Concurrently, compensatory metabolic and vascular mechanisms are initiated to enhance neuronal function [4]. Tight metabolic control is essential for normal brain function and survival. The relationship between metabolism and neuronal activity likely involves various complex regulatory pathways [5].

3.3.1 Oxygen

The brain is the largest consumer of energy in the body. With a mass of only 2–3% (1200–1400 g) of total body mass, the brain uses 20% of the total body oxygen consumption, 25% of total glucose consumption, and receives 15–20% of the cardiac output at rest [6, 7]. In children, total body oxygen consumption can be as high as 50% by 5 years of age [8].

Energy expenditure by the brain can be classified into two broad categories: (1) “activation energy” is the energy expended by the brain in the work of generating electric signals and consumes 55% of the total cerebral energy consumption and (2) basal metabolic processes consume the remaining 45% of the brain’s energy production [9]. The “activation energy” is used to generate adenosine triphosphate (ATP) and support neuronal electrical activity. This energy is primarily utilised at the synapse to drive ion pumps and sustain and restore ionic gradients and neuronal membrane potentials after depolarisation. Energy for the basal metabolic processes is needed to maintain cellular integrity and homeostasis with such processes including membrane stabilisation, ion pumping to preserve membrane ion gradients, and synthesis of structural and functional molecules [10]. Neurotransmitter synthesis, vesicle recycling, and axoplasmic transport contribute to the elevated metabolic requirements in neurons [5].

The normal human brain consumes oxygen at a rate of 156 μmol/100 g tissue/min in the conscious state. The production of CO2 is the same, leading to a respiratory quotient of quotient of 1.0 [11]. The cerebral metabolic rate (CMR) of oxygen consumption (CMRO2) in a normal, conscious, young adult is approximately 3.5 ml/100 g brain/min with a range of 3–3.8 ml/100 g/min equating to approximately 50 ml/min in adults. This energy consumption continues throughout the day and night and may be increased during rapid eye movement (REM) sleep [5, 8]. Energy requirements are not uniformly spread throughout the CNS. Requirements parallel cortical electrical activity and are greatest in the grey matter of the cerebral cortex.

The brain is absolutely dependent on an uninterrupted supply of oxygen to drive oxidative metabolism for the maintenance of structural and functional integrity. The brain has no O2 stores itself, and unconsciousness will occur after 10 s of complete cessation of blood flow. The critical level of O2 tension in the brain lies between 15 and 20 mmHg. Cessation of blood flow is followed within a few minutes by irreversible pathological changes within the brain [8]. Within 3–8 min all ATP stores will be depleted, leading to irreversible injury. The hippocampus and cerebellum are most sensitive to this injury. Cerebral metabolism of oxygen may be impaired in various disease states including stroke, traumatic brain injury, and Alzheimer’s disease [11].

3.3.2 Energy Substrates

Most tissues in the body operate facultatively in choosing energy substrates with an ability to use such substrates interchangeably according to their availability. The brain does possess the capacity to utilise various substrates for metabolism to generate the energy requirements for its numerous needs. Such substrates include glucose, ketone bodies, lactate, glycerol, fatty acids, and amino acids. However, in vivo the brain appears inflexible in substrate choice with glucose, by far, the primary source of energy.

The rate of brain glucose utilisation is estimated as 31 μmol/100 g/min [12]. Carrier-mediated mechanisms account for the majority of glucose transport with only 4% of glucose entering via simple diffusion [9]. The transport of glucose through cell membranes of neurons is not dependent on insulin.

Cellular respiration to metabolise glucose for energy release in the form of ATP occurs in two sequential phases. Glycolysis occurs in the cytosol of cells without the influence of oxygen and results in the production of two molecules of ATP and pyruvate per molecule of glucose, the pyruvate being subsequently converted to lactate. Oxidative phosphorylation occurs on the inner mitochondrial membrane and, in the presence of oxygen, produces 36 molecules of ATP. In the resting brain, aerobic metabolism accounts for 99% of energy production and is directly related to glucose consumption [10].

Cerebral glycogen stores are limited to approximately 0.3–0.4 μmol/100 g tissue [13] providing only a 2-min supply of glucose generated from glycogen in the neurons. Glucose deprivation results in aberrations of cerebral function with mental state changes from mild sensory disturbances to coma. These clinical effects, paralleled by abnormalities in EEG patterns and the CMR [12], are independent of decreased cerebral blood flow (CBF). In special situations, the energy needs of the brain may be partly fulfilled with substrates other than glucose. During starvation and ketosis, for example, ketone bodies (acetoacetate and β-hydroxybutyrate) become the major source of energy substrates [14].

In the brain, as in other tissues, glycolysis results in pyruvate that is subsequently converted into lactate. In some situations, such as immediately after injury, there may be a relative increase in glycolysis, termed “hyperglycolysis” that leads to increased lactate production [15]. The CMR for lactate depends on the balance between production, uptake, and disposal [16]. In humans the extent of lactate production is typically overlooked because production is balanced by removal rate. However, the role of lactate may be under-appreciated. Lactate may have a significant role in normal and pathophysiological states.

3.3.3 Neurometabolic Coupling

Lactate exchange, termed “lactate shuttle”, may occur among various cellular sites of production and removal [17]. It has been postulated that a similar process occurs in the brain [18]. Such exchanges among neurons and other cells depend on the metabolic rates within cells and on the extracellular environment influenced by cellular metabolism and vascular delivery and removal [19]. Cellular compartmentalisation of bioenergetics has been suggested with different phases occurring in different cell types [20]. Glucose in the cerebral circulation is thought to be primarily consumed anaerobically by astrocytes. The resultant lactate released into the extracellular space is thought to be consumed aerobically by neurons [21]. The close association of astrocytes with capillaries and neuronal synaptic clefts allow them to crucially regulate neurometabolic coupling during neuronal activity by, for example, maintaining neurotransmitter stores via the glutamine-glutamate cycle [5]. This is supported by distinct gene expression patterns and expressions of, for example, lactate transporter proteins in astrocytes and neurons. This coupling of neuronal activity to astrocytic glycolysis suggests a far more complex cerebral bioenergetic process than previously considered.

3.4 Cerebral Blood Flow (CBF)

Total CBF in adults is approximately 50 ml/100 g tissue/min with a range of 50–60 ml/100 g/min [22]. Levels are usually higher in children and adolescents and decreases with age [23]. The flow varies to the different tissues with grey matter receiving 80 ml/100 g/min and white matter 20 ml/100 g/min. Total CBF is thus approximately 750 ml/min (range 750–900) in an adult which constitutes 15–20% of the cardiac output. The brain does not tolerate any major drop in perfusion. A CBF of less than 20–25 ml/100 g/min can lead to cerebral impairment. Flows of 15–20 ml/100 g/min cause a flat EEG, and anything less than 10 ml/100 g/min will cause irreversible brain damage.

The CBF depends on the arterial blood pressure, the intracranial pressure (ICP), or back pressure in the cerebral venous system, and the resistance of the small cerebral vessels. Cerebral vessels rapidly adapt to the chemical environment of the brain, neuronal signals and to pressures within the vessels themselves. Maintenance of optimal CBF relies on the relationship between cardiovascular, respiratory, and neurological physiology [22].

3.4.1 Cerebral Metabolic Rate of Oxygen Consumption

The lack of significant brain storage capacity necessitates tight coupling of cerebral metabolism, CBF, and oxygen extraction. Fick’s equation best describes this relationship:

$$ {\mathrm{CMRO}}_2= CBF\times {\mathrm{AVDO}}_2 $$

(CMRO2 = cerebral metabolic rate of oxygen; CBF = cerebral blood flow; AVDO2 = arterio-venous difference of oxygen)

The CBF thus varies with brain metabolic activity (Fig. 3.6). Neurovascular and neurometabolic coupling mechanisms enhance blood flow and utilisation of metabolism to compensate for varying energy demands throughout the brain [5]. Regional CBF is directly related to metabolic activity in that area, e.g. moving an arm. Regional blood flow ranges from 10 to 300 ml/100 g/min. This flow-metabolism coupling or “functional hyperaemia” may be the most relevant of the CBF regulation mechanisms, as cerebral tissue is among the least tolerant of ischemia [25].

Fig. 3.6
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Linear relationship between CBF and CMRO2 (From Nordstrom et al. [24]—Creative Commons Attribution 4.0 International License)

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3.4.2 Cerebral Perfusion Pressure

The pressure that supplies the cerebral vessels is dependent on arterial blood pressure, which in turn is dependent on factors outside the brain, namely cardiac output and the peripheral vascular resistance. Any physiological or pathological event affecting these factors has the potential to affect CBF. The CBF is also impaired by conditions that increase ICP or impede cerebral venous outflow. Cerebral perfusion pressure (CPP) is therefore related to both the mean arterial pressure and the back pressure, i.e. the higher of either ICP or CVP (central venous pressure):

$$ CPP=\mathrm{MAP}\hbox{--} ICP\ \left(\mathrm{or}\ CVP\ \mathrm{if}\ \mathrm{higher}\right) $$

The normal CPP is approximately 80–100 mmHg. Levels of ICP >30 mmHg compromise CPP and CBF. Levels of CPP <50 mmHg demonstrate slowing on EEG, 25–40 mmHg produce a flat EEG, and <25 mmHg cause irreversible brain damage.

3.4.3 Autoregulation

Cerebral autoregulation is the homeostatic phenomenon under normal conditions whereby cerebral vessel caliber is changed in response to changes in cerebral metabolism and/or CPP in order to regulate and maintain a constant CBF across a range of blood pressures. Cerebral vascularity has the ability to rapidly adapt to changes within 10–60 s. A decreased CPP will cause cerebral vasodilation, whereas an increased CPP will lead to vasoconstriction.

The CBF is maintained at a constant level between mean arterial pressures (MAP) of 60–160 mmHg. For MAPs outside these limits, CBF becomes pressure dependent (Fig. 3.7). Levels of MAP >150–160 mmHg can disrupt the blood–brain barrier (BBB) and may cause cerebral oedema or haemorrhage. In chronic hypertensive patients, this curve is shifted to the right to offer protection to the higher arterial pressures.

Fig. 3.7
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Relationship between CBF and MAP (From Harary et al. [26]—Creative Commons Attribution 4.0 International License)

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The major site of active regulation is thought to be at the level of the arterioles because of the thick smooth muscle layer and the ability to rapidly constrict and dilate. Conversely cerebral veins and venules have a low density of smooth muscle cells and react to increases in pressure with increasing volume. In healthy individuals, this is most evident during neuronal activity which elicits a significant increase in CBF through vessel dilation. However, during ischaemic stroke or vasospasm, cerebral arteries constrict, causing a local increase in cerebral vascular resistance and, by extension, a decrease in CBF [22].

Various mechanisms have been proposed to account for the changes in vascular tone of cerebral vessels. The myogenic mechanism proposes a response of vascular smooth muscle to transmural pressure changes that occurs through arterial membrane depolarisation, with a resultant change in the concentration of Ca2+ in the arterial wall [27]. The metabolic mechanism proposes that altered concentrations of vasoactive metabolites (such as adenosine) resulting from initial blood pressure-induced changes in blood flow accounts for changes in vascular calibre [28]. In the neurogenic mechanism, perivascular neurons are proposed to have autoregulatory effects on cerebral arterioles via an extensive arborisation of perivascular nerves [29].

Neurovascular coupling, first described by Roy and Sherrington, refers to the relationship between local neural activity and subsequent changes in CBF [4]. The exact mechanism for this activity-coupled increases in local CBF remains unclear. Glutamate release following synaptic transmission may be a key stimulus for neurovascular coupling through production of vasoactive metabolites which include arachidonic acid derivatives, adenosine, lactate and nitric oxide. These substances produce changes in intracellular calcium concentration in the smooth muscle fibres of the arterioles or capillaries, altering the degree of vessel constriction [22]. Of these metabolites, nitric oxide (•NO) may play a key role [30]. Astrocytes are also thought to play a key role in regulating blood flow. The processes from these cells ensheath brain capillaries. During neuronal activation, Ca2+ release triggered at astrocytic end feet induces pathways downstream that regulate vasodilation [31].

3.4.4 Extrinsic Regulatory Mechanisms

3.4.4.1 Respiratory Gas Tensions

Blood and CSF tension of respiratory gases affect cerebral blood flow (Fig. 3.8). Cerebral vasculature is extremely sensitive to changes in PaCO2 and levels between 20 and 60 mmHg are directly related to CBF. A decrease in PaCO2 constricts cerebral resistance vessels, while an increase leads to dilation. The CBF increases by 1–2 ml/100 g/min per mmHg change in PaCO2. A 70% increase in PaCO2 doubles CBF. Extracellular H+ concentration resulting from diffusion of PaCO2 probably plays an important role. Changes in CBF secondary to fluctuations in the pH of CSF and brain tissue occur immediately. PaCO2 of <20 mmHg shifts the oxyhaemoglobin dissociation curve to the left and may cause cerebral impairment. The PaO2 only influences CBF if marked changes occur. Hyperoxia causes a minimal decrease of approximately 10% in CBF, whereas PaO2 < 50 mmHg greatly increases CBF.

Fig. 3.8
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Relationship between CBF and respiratory gas tensions. The autoregulatory curve depicting CBF according to shifting PaCO2 resembles a sigmoid function with a CO2 reactivity zone between 20 and 60 mmHg. (1 Torr = 1 mmHg). (From Godoy et al. [32]—Creative Commons Attribution 4.0 International License)

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3.4.4.2 Temperature

The CBF changes by 5–7% per 1 °C change in temperature. Hypothermia decreases CMR and CBF. Conversely, hyperthermia increases CMR and CBF. Between 17 and 37 °C, for every 10 °C drop in temperature, CBF halves. At 20 °C the EEG is isoelectric and with temperatures >42 °C neuronal cell injury can occur.

3.4.4.3 Viscosity

A decrease in haematocrit decreases the viscosity of blood, causing an increase in CBF but also decreasing the O2 carrying capacity. Conversely, an increase in haematocrit will cause a decrease in CBF. The ideal haematocrit still remains controversial but is thought to be about 30% (30–34%).

3.4.4.4 Autonomic Influences

Intracranial vessels are innervated by both sympathetic and parasympathetic fibres. Sympathetic activity causes vasoconstriction and leads to a decrease in CBF. Conversely, parasympathetic activation causes vasodilation and increases CBF. This may play an important role in vasospasm after brain injury or stroke. Sympathetic innervation arises from the superior cervical sympathetic ganglia in the neck and travels into the brain along with the cerebral arteries. Mild to moderate stimulation or transection will have little effect. Blood flow autoregulation mechanisms can override the nervous system effects. Increased MAP caused by the sympathetic nervous system constricts large- and medium-sized arteries to prevent pressure reaching the smaller vessels. This can be preventative of vascular haemorrhage or “cerebral stroke”.

3.5 Blood–Brain Barrier

The preservation of normal brain activity requires a narrow and stable homeostatic environment. For this to occur, dynamic ion balance is needed, effective nutrient transport must occur and there must be a functional barrier to harmful molecules, toxic substances, and infective agents at the interface of the CNS and circulatory system [33]. Key in achieving this is the BBB.

3.5.1 Structure and Function

The BBB is a tightly regulated boundary between the CNS and the peripheral circulation that consists of three barrier layers: (1) a highly specialised endothelial cell layer separating blood and brain interstitial fluid, (2) the choroid plexus epithelium forming the blood-cerebrospinal fluid (CSF) barrier, and (3) the arachnoid epithelium that separates blood from the subarachnoid CSF [34]. Loss of function of this barrier is a major pathophysiological mechanism in many neurological diseases.

Capillaries in the CNS consist of a single, non-fenestrated, continuous layer of specialised endothelial cells with each cell encircling the microcapillary. The endothelial cells are highly polarised with distinct apical and basolateral compartments [35]. This polarity is demonstrated in the vital barrier properties that maintain the functioning and integrity of the BBB [36]. Substances from the microcapillary to the brain must travel either via the paracellular or the transcellular route [37]. The endothelial cells are nearly fused with tight junctions that form a barrier to ions and small hydrophilic molecules [38]. Tight junctions are composed of tight junction proteins such as occludin and claudin, adhesion junction proteins such as cadherin, junctional adhesion molecules and adaptor proteins such as zona occludens. CNS endothelial cells have limited vesicle-mediated transcellular movement (transcytosis) [39]. CNS endothelial cells use polarised cellular transporters for nutrient influx (e.g. glucose transporter 1) and efflux of toxins and metabolic wastes via ATP-binding cassette transporters [40]. CNS endothelial cells lack leukocyte adhesion molecules that prevent immune cell entry making the healthy brain immune-privileged [41].

The endothelium is further surrounded by pericytes and astroglial foot processes forming an additional continuous stratum [34]. There is some distance between the endothelial cells and brain tissue around the penetrating vessels. These form the Virchow–Robin space in which perivascular macrophages are found. The intimate contact and functional interactions and signalling between neurons, microglia, pericytes, astrocytes, and blood vessels form a dynamic functional unit, the neurovascular unit that is capable of rapid response to stressors (Fig. 3.9) [34, 37]. The basement membrane, a 30–40 nm thick lamina encloses pericytes and endothelial cells and is closely adjacent to the astrocyte end feet surrounding the cerebral capillaries. Astrocytes play a key role in maintenance of the BBB and homeostasis of extracellular transmitters, ions, metabolites, and water [34].

Fig. 3.9
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Schematic representation of the neurovascular unit at the capillary level. The blood–brain barrier is composed of several cell types and extracellular matrix molecules in close association. Highly specialised and polarised endothelial cells, basal lamina, pericytes, and astrocyte end feet, which by wrapping the micro-vessel walls, establish communication with neurons in the neurovascular unit. The neurovascular unit is important to maintain optimal brain function. Pericytes and astrocytes are important in barrier induction and maintenance. Microglia are CNS-resident immune cells. AQP—aquaporins; (Diagram by de Spohr, TCLS. Adapted from Abbott, 2013). (From Dubois et al. [42]—Creative Commons Attribution 4.0 International License)

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Areas of the brain such as the area postrema, pineal gland, and median eminence do not possess a BBB and are collectively termed the circumventricular organs. The barrier properties of such areas are significantly reduced so as to allow for easy transfer of molecules to and from the bloodstream [43].

The three BBB layers provide a physical and functional barrier affecting transport, metabolic, and immunological functions in a dynamic manner. Factors determining transport across the BBB include the size, charge, lipid solubility, and degree of protein binding of substances. Lipid-soluble substances pass through via diffusion. The BBB is permeable to O2, CO2, and other gases such as helium, xenon, nitrogen, and anaesthetic agents. The BBB is also permeable to water. Ionised and large molecules enter the brain in a restricted and regulated manner through the BBB. The BBB plays a role in CNS immunity by regulating the recruitment of leukocytes and innate immune elements. Loss of integrity of the BBB leaves the brain vulnerable to potentially harmful concentrations of substances. This may have a detrimental effect on brain homeostasis and neuronal signalling [37].

3.5.2 Transport of Glucose and Amino Acids

Essential polar molecules such as glucose, amino acids, and nucleosides cannot diffuse through the cell membrane and therefore enter via passive or secondarily active carrier-mediated influx. A family of glucose transporters (GLUT) is expressed by different cells. Endothelial cells of the microvasculature, astrocytes, and the choroid plexus express the insulin independent glucose transporter GLUT1 [34]. GLUT1 expression is upregulated by hypoglycaemia. The GLUT 4 transporter is also expressed in the BBB. GLUT3, expressed in neurons, likely provides glucose uptake into neurons. This uptake bypasses the glucose lactate shuffle through astrocytes that provides lactate as an energy substrate [34]. A sustainable supply of essential amino acids across the BBB is dependent on specific solute carriers expressed in the endothelium. As part of brain protection, the BBB is largely impermeable to neuroactive substances, e.g. aspartate and glutamate.

3.5.3 Transport of Ions

Specific ion channels and transporters act to preserve an optimal environment for synaptic and neural functioning. The BBB is largely impermeable to most ions thereby defending neural cells against significant variations in ion concentrations that may affect neuronal activity. Neuronal firing and synaptic transmission are associated with the influx of Na+ and Ca2+ and an increase in the concentrations of K+ and neurotransmitters extracellularly. However, regulated ionic movement maintains potassium concentration in the CSF and brain interstitial fluid at ~2.5–2.9 mM despite higher plasma concentration of potassium. The BBB is largely impermeable to ions such as Ca2+ and Mg2+. Astrocytes have an important role in maintaining brain extracellular environment despite continuous neuronal activity [34]. Water moves freely with bulk flow but depends on the presence of aquaporins.

3.5.4 Transport of Macromolecules

The presence of certain proteins and peptide macromolecules in the brain can initiate cascades that may lead to seizure activity, synaptic plasticity, and cell damage. Regulated movement of such molecules across the BBB is thus vital. Endocytic vesicles provide the main delivery of large molecular weight proteins and peptide molecules across the BBB by the process of transcytosis. Internalisation into the endothelial cell cytoplasm and exocytosis to the opposite pole accounts for transport of these molecules. This process may be receptor-mediated, for example, with insulin or adsorptive-mediated, for example, with cationised albumin [34].

Figure 3.10 summarises the movement of various substances across the BBB. The BBB can be disrupted by a multitude of factors including severe hypertension, tumours, stroke, trauma, infection, CO2, O2, and sustained seizure activity. In these situations, movement of the various substances becomes affected. Fluid movement, for example, becomes dependent on hydrostatic pressures more than osmotic gradients.

Fig. 3.10
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Potential routes for infiltration and transport across the endothelial cells forming the blood–brain barrier. (From Vidu et al. [44]—Creative Commons Attribution 3.0 Unported License)

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3.6 Cerebrospinal Fluid

Within the rigid bony structure of the cranium, the brain is vulnerable to mechanical trauma. To protect the brain and spinal cord, it is suspended in a specialised extracellular fluid that fills the ventricular and subarachnoid spaces. This CSF serves many roles to preserve optimal nervous system functioning. The CSF has a protective purpose by preventing deformation and damage caused by acceleration and deceleration during head movement. The buoyancy effect of CSF is thought to reduce the effective weight of the brain to about 25 g. This allows the brain to maintain its density without compression of its blood supply. It also has a key role in maintaining homeostasis by regulating fluid and electrolyte composition, transporting essential molecules, removal of substances, and is proposed to be involved in brain development and health [45]. The CSF represents an alternate point of entrance and exit for some substances that are not able to cross the BBB.

3.6.1 Production and Secretion

The production of CSF mainly occurs within the choroid plexuses in the lateral, third and fourth ventricles. Some production also occurs in the ventricular ependymal cell linings. The choroid plexus, comprised of microvilli and granular meningeal protrusions that extend into the ventricles, has a vast capillary network and filters plasma passively down a pressure gradient through the fenestrated capillary endothelium into the choroidal interstitial space. The epithelial cells of the choroid plexus are joined to the arachnoid membrane cells by tight junctions, limiting passive flow of water and are referred to as the blood–CSF barrier.

Active transport is required for the ultrafiltrate of plasma from the choroidal interstitial spaces, across the choroidal epithelium into the ventricular space, a process regulated by carbonic anhydrase and other membrane ion carrier proteins. Facilitated by aquaporin I in the apical membrane, water follows the osmotic gradient created by ATP-dependent ion pumps transporting Na+, Cl−, K+, and HCO3− into the ventricles. CSF volume and composition is closely regulated by the bidirectional flow of ions facilitated by Na/K2/Cl co-transporters in the choroidal membrane. Fluid leaking from interstitial and perivascular spaces at extrachoroidal sites probably contribute minimally to production of CSF.

The gap junctions found in the pial and ependymal linings allow free diffusion between CSF and the extracellular space of the brain (ECSB). The CSF-ECSB may thus be considered a collective compartment with CSF playing an important part in homeostasis of the ECSB and brain tissue [46]. The variable distance of different cerebral tissues to the ECSB makes equilibration slow and transient differences may occur.

In a young, healthy adult, CSF is produced at a rate of about 400–600 ml/day which equates to approximately 21 ml/h. With a turnover rate of 4–5 times/day, the total amount of CSF around the brain at any given time is about 150 ml, with one-sixth of this volume filling the ventricles and the rest suspended in the subarachnoid space around the brain and spinal cord.

The volume and composition of CSF is finely regulated by multiple factors that influence the production and secretion of CSF. Autonomic innervation of the choroidal cells increases CSF secretion via cholinergic stimulation and conversely decreases secretion by sympathetic stimulation. Raised ICP has a minimal influence on the rate of CSF production as long as the CPP is above 70 mmHg. The decrease of the pressure gradient will minimally decrease filtration and secretion of CSF to act as compensation for rising intraventricular pressure, but this capacity to adapt is limited and rapidly exhausted. However, when CPP drops to below levels of 70 mmHg, CSF secretion decreases because of reduced cerebral and choroid plexus blood flow. Monoamine and neuropeptides play a role in CSF secretion. Both atrial natriuretic peptide and arginine vasopressin have been shown to decrease secretion. Aquaporins, enzymes, and membrane carrier proteins involved with CSF are influenced by humoral regulation and acid base disorders. The activity of carbonic anhydrase is also influenced by acid base disorders and carbonic anhydrase inhibitors. The production of CSF is decreased by several other pharmacological agents including corticosteroids, spironolactone, furosemide, isoflurane, and vasopressors [45].

3.6.2 Composition

CSF is mainly composed of water. The osmotic pressure of CSF approximates that of plasma. The hydrostatic pressure of CSF is 5–15 mmHg with a pH of 7.32. The composition of CSF differs greatly from plasma. Although CSF concentration of Na+ ions is similar to plasma, Cl− and Mg2+ concentrations are higher, whereas K+ and Ca2+ concentrations are lower. The osmolality of CSF is maintained by bulk flow of H2O molecules. Small amounts of plasma proteins, mostly albumin enter the CSF either via passing through epithelial cell junctions or via vesicular transport across the epithelial cells at the choroid plexus. A minimal amount of protein can enter via extrachoroidal sites or via bulk flow from the extracellular space of the brain. CSF therefore has a protein concentration that is much lower than that of plasma (0.025 g/100 ml versus 7 g/100 ml) [47]. The ratio of glucose levels in CSF to plasma is about 0.6 and the cell count is usually less than 5 cells/ml. Microglial cells constantly remove unwanted or damaged tissue into the extracellular cerebral space and CSF, thus also contributing to CSF composition. The presence of certain immunological tissues or leukocytes in the CSF indicates possible neural damage and/or inflammation.

The CSF contains other substances and micronutrients including growth factor, vitamins B1, B12, and C, folate, B2-microglobulin, arginine vasopressin, nitric oxide (NO), peptides, proteins, and other ions that are thought to contribute to tissue repair, giving merit to the proposed idea of CSF being a “nourishing liquor” [47]. This is true for many ions and some organic molecules found in CSF but not for macronutrients which are not able to pass into CSF. The transfer of drugs via the CSF is finely regulated and depends mainly on size, charge, lipid solubility, and plasma protein binding of the drug.

3.6.3 Circulation

CSF circulates continually around the brain and spinal cord to maintain homeostasis. It flows to the beat of the systolic pulse wave but is also affected to a lesser extent by respiratory waves, posture, and physical effort, and is assisted by beating ciliated ependymal cells.

The CSF flows from the lateral ventricles toward the cisterna magna. Through the intraventricular foramen of Monro, CSF enters the third ventricle and exits via the aqueduct of Sylvia to the fourth ventricle. From here it passes to the cerebellomedullary cisterns via the lateral foramen of Luschka and the midline foramen of Magendie. Even though flow was previously thought to be unidirectional, oscillatory bidirectional flow through the aqueduct of Sylvia, propagated by the arterial pulse, respiration, and posture is now thought to occur [48]. These gentle ebbs and flows create mixing of CSF. However, the net flow of about 0.4 ml/min still remains from the ventricles toward the basal subarachnoid spaces. Multidirectional flow in the subarachnoid space circulates CSF around the brain and spinal cord.

3.6.4 Absorption

Absorption of CSF into the bloodstream occurs mainly via the arachnoid villi, and to a lesser degree, through the lymphatic system. Arachnoid granulations are responsible for the absorption of CSF via a dynamic pressure gradient dependent process. Finger-like villi are present over the cerebral hemispheres and in the spinal nerve roots. These are endothelium lined protrusions that facilitate translocation of CSF through vesicular passages into large venous sinuses that drain into the internal jugular system. Approximately 85–90% of CSF absorption occurs in the cerebral villi, and the rest in the spinal arachnoid villi. Free flow of large particles and proteins including red and white blood cells occur along a pressure gradient, provided this gradient remains greater than about 3–5 mmHg [47]. In the event of raised CSF pressure above 7 mmHg, absorption of CSF increases. This is accomplished by the development of more arachnoid villi increasing the surface area for absorption. Increased pinocytosis and opening of intercellular spaces also contribute to the increased absorption rate. As ICP increases, so does the absorption rate of CSF in a linear fashion up to an ICP of 30 cm H2O, at which point no further increase in absorption rate is possible. Conversely, increased venous pressure caused by obstruction, either of the internal jugular venous system or obstruction of villi in diseased states, decrease the pressure gradient, thereby decreasing absorption of CSF. Posture is also thought to influence absorption rate to a minimal degree.

To a lesser extent, CSF is also absorbed through the nasal cribriform plate and along the nerve root sleeves of cranial and spinal nerves providing a direct route to the extracranial lymphatics. Experimental data suggest a possible alternate pathway involving the Virchow–Robin perivascular spaces found around penetrating arteries and veins which lead directly to the cervical lymphatics [49]. As the brain and spinal cord lacks any lymphatic tissue, this process acts to return perivascular and interstitial protein to the blood.

3.6.5 Pathophysiology Related to Cerebrospinal Fluid

Inflammation and bleeding into the subarachnoid space can interfere with normal physiology and disruption of CSF homeostasis, resulting in altered secretion or absorption of CSF. Subarachnoid haemorrhage (SAH) and intraventricular bleeding caused by the disruption of a vessel into the subarachnoid space may cause obstruction of CSF flow in the ventricles. Inflammation leads to scarring, and further obstruction of arachnoid granulations occur. The resulting hydrocephalus and raised ICP explain the classic symptoms of headache, nausea and vomiting, seizures, vision disturbances, and loss of consciousness or death associated with SAH. Analysis of CSF will demonstrate erythrocytes or visible xanthochromia.

3.7 Intracranial Pressure

Intracranial pressure (ICP) refers to the pressure of the contents within the cranial vault. The ICP is a key determinant of the CPP. In many CNS disease states the contributing pathophysiology that results in brain death is as a result of cerebral oedema and intracranial hypertension. Understanding the changes in ICP in pathologies such as head trauma, subarachnoid haemorrhage, and intracranial tumours helps to better manage these conditions in the quest for better outcomes.

3.7.1 Volume/Pressure Relationship

The cranial vault is a rigid compartment with a fixed total volume consisting of the brain (80%), blood (12%), and CSF (8%). The Monro–Kellie hypothesis states if an increase occurs in the volume of one component, the volume of one or more other components must decrease, or ICP will be elevated. Physiological values of ICP range between 3 and 4 mmHg before the age of 1 year, and between 10 and 15 mmHg in supine adults. Respiration and the cardiac cycle lead to cyclical variations in ICP. The ICP also varies with body position and clinical conditions. Coughing, sneezing, and straining may transiently increase ICP to 30–50 mmHg.

The capacity of the intracranial contents to adapt to volume changes is defined as brain compliance (Fig. 3.11). Changes in the CSF and blood components are the initial buffer mechanisms to defend the ICP. Compensatory CSF pressure changes are regulated at all levels including CSF displacement from cranial to spinal space, decreased CSF secretion and circulation, and increased CSF absorption. An increased intraventricular pressure decreases the pressure gradient across the blood–CSF barrier at the choroidal plexus. Neuropeptides such as atrial natriuretic peptide and arginine vasopressin decrease choroidal secretion of CSF and cause pial artery dilation. Compensatory changes in the blood component are from a decrease in the total cerebral blood volume with the venous component primarily affected. Other CBF regulatory mechanisms are covered in the preceding section on CBF.

Fig. 3.11
figure 11

Pressure–volume curve for ICP. Four “zones” may be delineated: (1) baseline intracranial volume with good compensatory reserve and high compliance (blue); (2) gradual depletion of compensatory reserve as intracranial volume increases (yellow); (3) poor compensatory reserve and increased risk of cerebral ischemia and herniation (red); and (4) critically high ICP causing collapse of cerebral microvasculature and disturbed cerebrovascular reactivity (grey) (Harary et al. [26]—Creative Commons Attribution 4.0 International License)

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3.7.2 ICP Waves

As the brain floats in the CSF, cardiac and respiratory pulse waves are transmitted intracranially to reflect a characteristic ICP waveform. The mean ICP is a reflection of the time average (Fig. 3.12a). Three components of the waveform are described: i) respiratory waveforms (0.1–0.3 Hz) associated with the respiratory cycle, (2) pulse pressure waveforms that are equal to the heart rate, and (3) slow vasogenic waveforms (e.g., “Lundberg A and B waves”). The pulse pressure waveform generated by the arterial pulse shows three distinct components (Fig. 3.12b). The percussion wave (P1) correlates with the arterial pulsation that is transmitted through the choroid plexus into the CSF. The P2 wave, also called the tidal wave, indirectly represents cerebral compliance as it is thought to be the arterial pulse wave reflecting off the brain parenchyma. The dicrotic wave (P3) reflects the pressure transmitted as a result of the aortic valve closure. All these waves are rarely more than 4 mmHg in amplitude, or 10–30% of the mean ICP. The ICP wave is usually in synchronisation with the QRS complex on the ECG or the arterial waveform on an invasive arterial line.

Fig. 3.12
figure 12

ICP pressure waves. (a) ICP fluctuations in response to the respiratory cycle (W2) and the arterial cycle (W1); (b) close-up of ICP waveform due to the systemic arterial cycle. Components are P1 (Percussion wave = representative of arterial pulsation), P2 (Tidal wave = a proxy for intracranial compliance), and P3 (Dicrotic wave = pressure transmission of aortic valve closure). A raised P2 wave is an indicator of raised ICP and reduced intracranial compliance (*). (Harary et al. [26]—Creative Commons Attribution 4.0 International License)

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The ICP waveform changes with any compromise of intracranial compliance. Lundberg first described the change in morphology in the global ICP waveform, observing three patterns [50]. (Fig. 3.13)

  • Lundberg “A” or plateau waves: periodic steep ramp, large amplitude (up to 50–100 mmHg) increases in ICP that persist for 5–20 min before returning to baseline. These waves can be observed in healthy asymptomatic individuals, but their long-term presence may be indicative of decreased CPP and poor prognosis.

  • Lundberg “B” waves: periodic, self-limited ICP increases of 20 to 50 mmHg lasting 1–2 min. These waves are related to changes in physiological or pathological CBF and may be due to cerebral vasospasm. They can progress to “A” waves.

  • Lundberg “C” waves: periodic, self-limited ICP increases of 20 mmHg occurring with a frequency of 4–8 per minute. They may result from the transmission of arterial pressure waves and have no pathological significance [52].

Fig. 3.13
figure 13

Lundberg waves. (From Nag et al. [51]—Creative Commons Attribution-Non-commercial License)

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Data from ICP recordings usually provide a global view of intracranial status. Such data need to be interpreted in conjunction with other general patient data and cerebral oxygenation and metabolic status from healthy and pathological territories of the CNS.

3.7.3 Increased ICP

The two main mechanisms of injury from increased ICP are cerebral ischemia and brain herniation. A level of ICP persistently raised above 15 mmHg is considered intracranial hypertension. Such a level decreases the CPP, and if prolonged, leads to focal and global ischaemia. High ICP (HICP) can cause secondary brain injury and death. HICP, traditionally defined as ICP > 20 mmHg, has been redefined as 22 mmHg [53]. However, a single threshold is controversial. Time spent above a threshold and its intensity (“ICP dose”) may be more important than the single threshold value [54]. Prolonged exposure to ICP values below the threshold may also be associated with poor outcomes [55]. If CPP is critically low, for example, as a result of a very low MAP, the utility of ICP for outcome prediction becomes limited.

Severe and sustained increases in ICP may lead to herniation of brain matter with resultant syndromes related to the sites of herniation, for example, transtentorial herniation of the uncus of the temporal lobe downwards through the tentorium, subfalcine herniation of the cingulate gyrus beneath the free edge of the falx cerebri and the potentially fatal tonsillar herniation of the cerebellar tonsils through the foramen magnum.

3.7.4 Intracranial Pressure Monitors

Various methods are available to measure intracranial pressure. Such methods may be broadly considered as invasive and non-invasive. Although non-invasive techniques minimise the risk of complications, invasive methods are still considered to be superior in accuracy [51].

3.7.4.1 Invasive Techniques

Invasive techniques measure intracranial pressure through fluid-filled systems or transducer-tipped catheters and can be used in a variety of anatomical locations including intraventricular, intraparenchymal, subarachnoid, subdural or epidural spaces (Fig. 3.14).

Fig. 3.14
figure 14

Potential sites for invasive monitoring of intracranial pressure. (Harary et al. [26]—Creative Commons Attribution 4.0 International License)

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3.7.4.1.1 External Ventricular Drainage (EVD)

Fluid-filled systems include the widely used and generally accepted gold standard technique of external ventricular drainage (EVD) [56]. The inexpensive catheter device placed through a burr hole into a ventricle has the added benefit of allowing drainage of CSF and can be recalibrated in vivo. It carries a risk of bleeding and infection. Trauma can be caused during insertion and these devices are prone to leaking and blockage [57].

3.7.4.1.2 Implantable Microtransducer ICP Monitoring Devices

Transducer-tipped catheters are directly placed in the intraventricular, intraparenchymal, subarachnoid or epidural space [56]. The most commonly used compartment is the parenchymal space. These devices are simpler to insert and not affected by blockage as with EVD systems. Bleeding and infection remain concerns. These devices are considered to be as accurate as EVDs, however, a significant disadvantage is that they have a higher cost and no recalibration is possible after placement [56]. Strain gauge, fibre-optic, microchip, and pneumatic sensor microtransducer devices are available. Fibre-optic devices transmit pressure dependent light through a fiberoptic cable to a movable mirror. The degree of movement of the flexible mirror changes the properties of the reflected light which is then translated into an ICP value [58]. Strain gauge devices calculate the change in resistance in the transducer in response to intracranial pressure [58]. Newer implantable devices are capable of telemetric ICP measurement wirelessly. These can be left in for several months with limited drift and may monitor ICP under normal daily living conditions in outpatient settings. The clinical use of such devices remains to be established.

3.7.4.1.3 Other Devices

Subarachnoid screws, bolts or catheters employ fluid-filled systems placed directly in the subarachnoid compartment. These devices are less prone to trauma and infection but tend to underestimate ICP [58]. Epidural and subdural devices are easier to insert and carry a lower risk of infection than EVDs. They, however, have low accuracy with sensor drift and cannot be calibrated in vivo. These devices are seldom used currently.

3.7.4.2 Non-Invasive Techniques

Non-invasive techniques in general measure physiological variables that indirectly correlate with ICP. Such techniques have less complications but are not as accurate as invasive techniques and are therefore not advocated for routine use.

Various non-invasive monitoring methods have been described [51, 56]. Transcranial Doppler Ultrasonography (TCD) measures the blood flow velocity in the middle cerebral artery. This technique requires training and experience and has significant intra- and inter-observer variability. Tympanic Membrane Displacement (TMD) measures the movement of the tympanic membrane caused by stimulation of the stapedial reflex. Optic Nerve Sheath Diameter (ONSD) is an affordable and efficient method but also requires training and is subject to intra-and inter-observer variability. Fundoscopy and observation of papilloedema is a subjective assessment. As papilloedema takes some time to develop it is not applicable in the acute setting and other causes of papilloedema should also be considered [56].

The choice of ICP monitor should be made on a case-by-case basis. Specific consideration should be given to the specific pathology and risk of bleeding of the patient as well as the accuracy and cost of the chosen technique and the possible mechanical problems of specific devices.

3.8 Conclusion

A clear and detailed understanding of central neurophysiology is essential to better appreciate the pathophysiology of subarachnoid haemorrhage. The complex components of the nervous system and their intricate interactions form the cornerstones of such an understanding. The essential electrophysiology, the balance of cerebral metabolism and blood flow, the importance of the blood–brain barrier, the complexity of cerebrospinal fluid, and the impact of intracranial pressure all serve to form a firm foundation in the study of brain pathologies.