Arterial Supply Venous Drainage
Functional Considerations Blood–Brain Barrier
77
heart attack or suffocation, the brain dies first.
Only if oxygen is restored to the brain in a few minutes will the brain retain its functional via-bility.
Blood is supplied to the brain by the internal carotid arteries and the vertebral arteries. It is drained from the brain largely by the internal jugular vein. The cerebral arteries, venules, and veins do not differ structurally from vessels of similar size and function in other organs. How-ever, the capillaries of the central nervous system (CNS) do differ significantly in ultra-structure and physiology from capillaries of the general circulation (see Blood–Brain Barrier).
ARTERIAL SUPPLY
The arterial blood supply to the brain is derived from two pair of trunk arteries: (1) the
vertebral arteries and (2) the internal carotid arteries (Figs. 4.1 and 4.2).
Vertebral Circulation
The paired vertebral arteries enter the cra-nial cavity through the foramen magnum and become located on the anterolateral aspect of the medulla (Fig. 4.1). They unite at the mid-line at the pontomedullary junction to form the basilar artery, which continues to the midbrain level, where it bifurcates to form the paired posterior cerebral arteries. The branches of the vertebral and basilar arteries supply the medulla, pons, cerebellum, mid-brain, and caudal diencephalon. Each poste-rior cerebral artery supplies part of the caudal diencephalon and the medial aspect (and adja-cent lateral aspect) of the occipital lobe including the primary visual cortex (area 17) and the inferior posterior temporal lobe. The
78 The Human Nervous System
Figure 4.1: Major arterial supply to the brain. The vertebral–basilar–posterior cerebral arterial tree is indicated as solid black vessels and the paired middle and anterior cerebral tree is indicated as white vessels. Note the circle of Willis, which comprises the single anterior communicating artery and the paired anterior cerebral, internal carotid, posterior communicating, and posterior cerebral arteries. The last paired arteries are formed by the bifurcation of the basilar artery. The circle of Willis is located beneath the hypothalamus and surrounds the stalk of the hypophysis and optic chiasm.
branches of the vertebral and basilar arteries that supply the medial aspect of the brainstem adjacent to the midsagittal plane are called paramedian arteries (anterior spinal artery, paramedian branches of the basilar artery);
those that supply the anterolateral aspect of the brainstem are called short circumferential arteries (branches of the vertebral artery, short pontine circumferential branches of the basilar artery); and those that supply the pos-terolateral and posterior aspect of the brain-stem and cerebellum (Figs. 17.1 and 17.2) are the long circumferential branches (posterior spinal artery, posterior inferior cerebellar artery, anterior inferior cerebellar artery, superior cerebellar artery).
Internal Carotid Circulation
Each internal carotid artery passes through the cavernous sinus as the S-shaped carotid siphon and then divides, level with and lateral to the optic chiasm, into two terminal branches:
(1) the anterior cerebral artery, which supplies the orbital and medial aspect of the frontal lobe and medial aspect of the parietal lobe, and (2) the middle cerebral artery, which passes later-ally through the lateral fissure between the tem-poral lobe and insula and divides into a number of branches supplying the lateral portions of the orbital gyri and the frontal, parietal, and temporal lobes (Figs. 4.1 and 4.3). Peripheral branches of the middle cerebral arteries anasto-mose on the lateral surface of the cerebrum with peripheral branches of the anterior and posterior cerebral arteries. Branches of the middle cerebral artery and the choroidal arter-ies penetrate the cerebrum to supply the basal ganglia, most of the diencephalon, internal cap-sule, and adjacent structures; these central or ganglionic branches (e.g., striate arteries) and the choroidal arteries are variable in their extent and in their anastomotic connections.
Other branches of the internal carotid arteries include the ophthalmic artery (to the orbit), the anterior choroidal artery (to the arc structures adjacent to the choroidal fissure; Chap. 5), and the posterior communicating artery (joins pos-terior cerebral artery).
Circle of Willis
Although the vertebral–basilar arterial tree and the internal carotid arterial tree are essen-tially independent, there are some anastomotic connections between the two systems (e.g., between the terminal branches of posterior Figure 4.2: Cerebral arterial circle (circle of Willis). The cerebral arterial circle consists of the following: (1) the proximal part of three major paired arteries: anterior, middle and pos-terior cerebral; (2) the short, single anpos-terior communicating artery that connects the ante-rior cerebral arteries; and (3) the longer, paired posterior communicating arteries that go between the middle and posterior cerebral arteries. The circle of Willis is supplied by two pairs of arteries (a) the vertebrals—branches of the subclavian arteries and (b) the internal carotids—branches of the common carotid arteries. Each internal carotid artery divides into an anterior cerebral artery and a larger middle cerebral artery. The arrows point to common sites of atherosclerosis and occlusion.
cerebral arteries and those of the anterior and middle cerebral arteries). The cerebral arterial circle of Willis (Figs. 4.1 and 4.2) is an arterial ring in which the two systems are connected by the small posterior communicating arteries.
The anterior communicating artery that connects the two anterior cerebral arteries completes the circle. There is actually little exchange of blood through these communicating arteries; the cir-cle of Willis can act as a safety valve when differential pressures are present among these arteries.
The arteries meeting at the cerebral arterial circle of Willis form branches comparable to
those of the basilar artery. Thus, (1) the ante-rior, middle, and posterior cerebral arteries are actually long circumferential arteries, (2) the subbranches (e.g., striate arteries; Fig. 4.1) of these three major cerebral arteries close to the circle of Willis are short circumferential branches, and (3) the small medial arteries aris-ing from the circle of Willis are paramedian branches.
Anastomotic connections within the verte-bral and internal carotid systems are extensive in the brain. Those that occur among the large branches of the superficial arteries on the sur-face are usually physiologically effective, so
80 The Human Nervous System
Figure 4.3: Distribution of the arteries on the surface of the brain. (A) lateral surface; (B) medial surface. Superior cerebellar artery.
that occlusion need not result in impairment of blood supply to the neural tissues. Rich anasto-moses do exist among the capillary beds of adjacent arteries within the substance of the brain, but occlusions of these arteries most often are followed by neural damage. The anas-tomotic connections might not be sufficient to allow adequate blood to reach the deprived region rapidly enough to meet its high meta-bolic requirements.
VENOUS DRAINAGE
The veins draining the brainstem and cere-bellum roughly follow the arteries to these structures. On the other hand, the veins drain-ing the cerebrum do not usually form patterns that parallel its arterial trees. In general, the venous trees in this region have short stocky branches that come off at right angles, resem-bling the silhouette of an oak tree.
Dural Sinuses
Venous anastomoses are extensive and effective between deep veins within the brain and superficial surface veins (Fig. 4.4). The veins of the brain drain into superficial venous plexuses and dural sinuses. The dural (venous) sinuses are valveless channels located between two layers of the dura mater. Most venous blood ultimately drains into the internal jugu-lar veins at the base of the skull.
The blood from the cortex on the upper, lat-eral, and medial aspects of the cerebrum drains into the superior sagittal (dural) sinus to the occipital region. From there, it flows to the transverse (lateral) and sigmoid sinuses into the internal jugular vein. All dural sinuses receive blood from veins in the immediate vicinity.
The deep cerebral drainage is to the region of the foramina of Monro, where the paired internal cerebral veins (posterior to the choroid plexus of the third ventricle) extend to the region of the pineal body. There, they join to form the great vein of Galen. Blood then flows, successively, through the straight sinus (located
along the midline within the tentorium, which is dura mater lying between the cerebellum and occipital lobe), transverse sinus, and sigmoid sinus before draining into the internal jugular vein (Figs. 4.4 and 5.1). The straight sinus also receives venous blood from the inferior sagittal sinus located along the inferior margin of the falx cerebri just above the corpus callosum.
Some blood from the base of the cerebrum drains into the superior and inferior petrosal sinuses and then flows into either the sigmoid sinus or the cavernous sinus in the region of the hypothalamus (on the sides of the sphenoid bone). The cavernous sinus is connected via the superior petrosal sinus with the transverse sinus, via the inferior petrosal sinus with the jugular vein, and via the basilar venous plexus with the venous plexus of the vertebral canal (Fig. 4.4).
Emissary Veins
Some dural sinuses connect with the veins superficial to the skull by emissary veins.
These veins act as pressure valves when intracranial pressure is raised and are also routes for spread of infection into the brain case (infection in the nose could spread via an emissary vein high in the nose into the meninges and could result in meningitis). The cavernous sinus is connected with emissary veins, including the ophthalmic vein, which extends into the orbit.
FUNCTIONAL CONSIDERATIONS The mean blood flow in the normal brain is 50 mL/100 g of brain tissue per minute. It takes about 7 seconds for a drop of blood to flow through the brain. At any given moment, how-ever, the flow through a specific region could be greater, the same, or less than the mean flow through the CNS. The brain is similar to other tissues of the body where the amount of blood flow varies with the level of metabolic and functional activity. For example, dynamic vol-untary movements of the hand are associated with an increase in the blood flow within the
82 The Human Nervous System
Figure 4.4: Venous drainage from the brain. (A) lateral view of the brain (*Location of emis-sary veins); (B) medial view of the brain.
cerebral cortical motor areas associated with hand movements and with sensory areas receiving signals from skin, joints, and muscles associated with these movements (Chap. 25).
Anastomotic connections within the verte-bral and internal carotid arterial systems form extensive patterns of collateral circulation in the brain. A sudden deprivation of the blood supply to a region of the brain could, if the vas-cular insufficiency lasts for more than a few minutes, result in the necrosis (infarct) of brain tissue. The inadequate oxygen and glucose sup-ply at the lesion (infarct) site is the essential cause of a “stroke” (sudden appearance of focal neurologic deficits). This could result from the sudden occlusion by a thrombus (blood clot formed within the blood vessel), or an embolism (a portion of clot transported along in the blood stream) to the occlusion site, or the rupture of an artery often the result of arte-riosclerosis or hypertension; this is called a cerebrovascular accident (CVA). A stroke is often preceded by a significant warning sign known as a ministroke or transient ischemic attack (TIA). These temporary spells are the result of impaired neural function caused by a brief but definite reduction in blood flow to the brain. Depending on the location that is deprived of oxygen and glucose, the symptoms might include difficulty in talking, temporary weakness or paralysis on one side, dizziness, blurred vision, loss of hearing, and so forth.
Interconnections among the large branches of the superficial arteries are usually physio-logically effective, so that an occlusion of one need not result in a marked impairment of the blood supply to the neural tissues. For example, following an occlusion within the circle of Willis, or its proximal branches, the collateral circulation is often adequate, especially if the involved artery becomes occluded slowly before the stroke. In contrast, anastomoses among the distal arterial branches of the circle of Willis are variable; consequently, the collat-eral circulation might not be adequate and occlusion of a vessel might result in an infarct.
Rich anastomoses exist among the capillary beds of adjacent arteries within the substance
of the brain, but an occlusion of the supplying arteries is often followed by neural damage, causing symptoms and signs correlated with the site (Chaps. 17 and 25). This occurs because the anastomotic connections are not suffi-ciently rich to allow adequate blood flow to reach the deprived areas rapidly enough to meet the high metabolic requirements.
An occlusion of the anterior cerebral artery results in a lesion of the paracentral lobule that has the general sensory and motor cortical areas for the contralateral lower extremity (Chap. 25). A lesion in this area results in con-tralateral paresis as a motor sign coupled with diminished sensitivity (hypoaesthesia) of the general senses in this extremity (Chap. 12).
Blockage of the calcarine branch of the poste-rior cerebral artery (which supplies the pri-mary visual cortex of one side) results in a contralateral hemianopsia (Chap. 19). Occlu-sion of small branches of the posterior cerebral artery (which supplies the posterior thalamus and adjacent tissues) produces the thalamic syndrome (Chap. 23). Strokes following the rupture and bleeding of the striate arteries, branches of the middle cerebral artery (which supply portions of the internal capsule and adjacent structures), result in signs that include an upper motoneuron paralysis of the face and upper and lower limbs on the opposite side as well as sensory disturbances (Chaps. 12 and 25). Signs associated with vascular lesions of branches of the vertebral artery supplying the brain stem are outlined in Chapter 17.
Although collateral circulation provides cer-tain regions of the CNS with a margin of safety during arterial occlusion, the anastomotic net-work also allows for a degree of vulnerability.
With a reduction in the systemic blood pres-sure, a region supplied by an anastomotic net-work is susceptible to ischemia; such an anastomosis occurs at the terminal ends of two or more arterial trees, a border region where perfusion pressure is lowest. These border regions, which are supplied by major arteries, are called border zones or watershed zones. An infarction occurring in such a region is called a border zone or watershed zone infarct.
BLOOD–BRAIN BARRIER
The blood–brain barrier (BBB) is a special-ized functionally dynamic structure that main-tains the microenvironment, thus enabling neurons to function effectively. Anatomically, the barrier consists of endothelial cells of the brain capillaries and their tight junctions (Fig.
4.5). The BBB’s role is accomplished by activ-ities that regulate the movement of various metabolites and other chemical substances between the blood and the brain by (1) exclu-sion, (2) selective passage, and/or (3) removal.
The capillary bed is comprised of endothelial cells with adjacent smooth-muscle-like peri-cytes and end-feet of astroperi-cytes that ensheathe the endothelial cells (Fig. 4.5). The contractile property of endothelial cells and the pericytes can alter the shape and size of a capillary lumen. Exclusion of blood-borne substances is largely regulated by the properties of the cell membrane of the brain’s endothelial cells. For example, this membrane limits the passive dif-fusion of H2O and certain aqueous substances from the blood. Selective passage of metabo-lites and chemical substances essential for the growth and function of the brain are conveyed (1) by the diffusion of some lipid-soluble sub-stances by ion channels and transport proteins (transporters) and (2) by facilitative and energy-dependent receptors that mediate the transport of water-soluble substances. These include the transport from blood to brain of amino acids, peptides, and the energy substrate glucose.
Removal of metabolites that accumulate in
excess is conveyed by transporters from brain to blood (Fig. 4.5).
The combination of the specialized cell membrane of the endothelial cells linked by intercellular tight junctions is the hallmark of the BBB (Fig. 4.5). This duo effectively excludes by blocking the passage of many sub-stances across the capillary wall. The perme-ability property can be enhanced by the state of phosphorylation of the proteins of the cell–cell adherens junctions. The cadherin proteins of the adherens junctions also act as a signaling component between endothelial cells through linkages with the cytoskeletal protein filaments of the endothelial cells. The presence of so few pinocytotic vesicles within the endothelial cells is indicative that the transcellular movement by vesicles across the BBB (transendocytosis) is both relatively deficient and slow. However, the selective passage of substances is related to the presence of high concentrations of carrier-mediated transport systems that act as trans-porters for glucose, essential amino acids, other required nutrients, and macromolecules. These ensure the passage of essential substances from the blood to the CNS. The perivascular astro-cytes with end-feet that ensheathe about 95%
of the capillary surface are not considered to be a component of the BBB. Some evidence sug-gests that the early proliferating perineural blood vessels, composed of primordial fenes-trated endothelial cells with no BBB, might be induced by brain-derived molecular signals from early perivascular astroglia to develop into endothelial cells lacking fenestrations and, thus, express BBB properties.
84 The Human Nervous System
Figure 4.5: Ultrastructural features of the specialized capillary endothelial cells of the brain compared to a general capillary. A,B: Brain capillary. The endothelial cells (ECs) have several anatomic features that contribute to the so-called blood–brain barrier (BBB). Transcellular passage of substances across the BBB from the blood to brain is regulated, in part, by the combination of restrictions, including specialized cell membranes of the ECs adjacent to the bloodstream, tight junctions between ECs, a scarcity of pinocytotic vesicles, and selective transport of water-soluble compounds by transendocytosis. The presence of abundant mitochondria supplies the energy-dependent transport system delivering substances required by the brain. The cell-to-cell adherens junctions contribute minimally to the BBB. The foot processes of the astrocytes that almost com-pletely ensheath the brain capillaries are not functional components of the BBB, but could influ-ence “barrier-specific endothelial cell differentiation.” Note the smooth muscle-like pericyte
adjacent to the capillary. C: General (systemic) capillary. In contrast, the relatively unselective dif-fusion across endothelial cells of other organs is enhanced by the presence of fenestra, interen-dothelial cleft passage of fluid, numerous pinocytotic vesicles, and few mitochondria and the absence of tight junctions.
The selective passage of essential sub-stances that must cross the BBB in sufficient quantities is primarily accomplished by the dif-fusion of lipid-soluble solutes and by facilita-tive and carrier-mediated transport of water-soluble substances. The great concentra-tions of mitochondria within the endothelial cells are indicative of high oxidative metabolic activity required by the carrier-mediated trans-port systems. This explains, in part, why small molecules pass through the barrier more rap-idly than medium-sized molecules and why large molecules such as serum proteins and penicillin do not pass through the BBB.
Diffusion
Lipid-soluble solutes such as O2, CO2, and some drugs pass rapidly from the blood through the barrier into the brain. Facilitated diffusion occurs “downhill” down a concentra-tion gradient because it is not energy depend-ent. Systems that move molecules rapidly without consuming energy act bidirectionally from the brain and cerebrospinal fluid to blood and vice versa, thereby influencing the passage to and from blood plasma and brain.
Carrier-Mediated Transport Systems
Most substances that must cross the BBB are not lipid soluble. They cross by facilitated diffusion and energy-dependent carrier-medi-ated active transporters (membrane-spanning proteins that facilitate the passage of small molecules), which are the conveyers of the numerous essential water-soluble substances such as glucose, amino acids, lactate, ribonu-cleosides, and several vitamins that cross the BBB. In these forms of transport, the solute (e.g., 99% of the glucose) combines with a spe-cific membrane carrier on one side of the bar-rier and then “shuttles” the solute across the barrier for release. These systems are efficient for transporting the glucose and other critical nutrients that must be supplied continuously and in a large quantity. Should the brain be inadequately supplied with sufficient glucose or oxygen, loss of consciousness and even death can occur within minutes.
An astrocyte might have processes with sev-eral end-feet that come in close contact with a capillary, with a neuron, and with the pia–glial membrane (Fig. 5.5). Thus, an astrocyte might have a transport function of transferring metabolites bidirectionally among the endothe-lial cells, neurons, and cerebrospinal fluid. . Astrocytes can (1) take up from the extracellu-lar fluid the excess potassium ions generated during intense neuronal activity and (2) regu-late the extraneural concentrations of neuro-transmitters by an uptake process and store them.
Activated lymphocytes, macrophages, and certain types of metastatic cell can cross the BBB barrier. These cells can recognize and bind to endothelial cells and then activate sig-naling systems that initiate transmigration junctional-opening mechanisms. Another per-meability barrier, called the blood–cere-brospinal fluid barrier, is present between the capillaries of the choroid plexus and the cere-brospinal fluid (Chap. 5).
The ependymal cells and subjacent astro-cytes (i.e., subependymal glial membrane) of the ventricles constitute a brain–cerebrospinal fluid interface (Fig. 5.6). The lateral cell sur-faces of the ependymal cells are comparatively simple without elaborate folds or interdigita-tions. This structural arrangement forms the brain-cerebrospinal fluid interface. Neither the ependymal surfaces of the ventricles nor the pia–glial membrane on the surface of the brain impede the exchanges of substances of between the cerebrospinal fluid and the capillaries of the brain. Thus, the brain–cerebrospinal fluid inter-face does not constitute a BBB.
Homeostasis of the neuronal environment is vital for the proper functioning of each neuron.
In turn, barriers are essential for the preserva-tion of homeostasis by maintaining the ionic constancy of the extraneuronal interstitial fluid (fluid surrounding the neurons, glial cells, and capillaries) by promoting the entry of required molecules, by preventing the entry of unwanted substances. and by removing unwanted sub-stances. Following infections, stroke, tumors, or trauma, the blood–brain barrier can be breached.
86 The Human Nervous System
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The meninges are three layers of connective tissue that surround and protect the soft brain and spinal cord. Cerebrospinal fluid (CSF) passes between two of the layers of the meninges and, thus, slowly circulates over the entire perimeter of the central nervous system (CNS). CSF also flows through the ventricles, which are the cavities within the brain derived from the central canal of the embryonic neural tube (Fig. 5.1).