Anastomoses at the circle of Willis and among the branches of distributing arteries protect the blood supply to the brain, which is ~15% of resting cardiac output
The brain accounts for only ~2% of the body's weight, yet it receives ~15% of the resting cardiac output. Of all the organs in the body, the brain is the least tolerant of ischemia. It depends entirely on oxidative sources of energy production. Each day, the human brain oxidizes ~100 g of glucose, N24-1 which is roughly equivalent to the amount stored as glycogen in the liver. Interruption of cerebral blood flow for just a few seconds causes unconsciousness. If ischemia persists for even a few minutes, irreversible cellular damage is likely.
Contributed by Emile Boulpaep, Walter Boron
As noted in Chapter 11 (see pp. 275 and 288), the brain has rather limited glycogen stores (~10% of the amount stored in the liver), and virtually all of these stores are in the astrocytes, which have mechanisms for transferring the energy to the neurons. As noted in the text on page 557, the glucose consumption by the brain alone is capable of exhausting the liver's entire store of glycogen in only 1 day. When food is not eaten for >24 hours, the brain must either rely on glucose derived from gluconeogenesis (largely from the breakdown of muscle protein) or utilize an alternative fuel. For example, as levels of ketone bodies rise in the bloodstream during fasting, the enzymes required for their oxidation are induced in brain cells, thereby enabling an alternative substrate for energy production and conserving lean body mass.
The text addresses related issues in three locations: (1) on page 557, (2) on page 287 (see Fig. 11-10), and (3) in Chapter 58 on metabolism.
Blood reaches the brain through four source arteries—the two internal carotid arteries and the two vertebral arteries (Fig. 24-1). The vertebral arteries join to form the basilar artery, which then splits to form the two posterior cerebral arteries, which in turn are part of the circle of Willis at the base of the brain. The internal carotid arteries are the major source of blood to the circle. Three bilateral pairs of distributing arteries (anterior, middle, and posterior cerebral arteries) arise from the circle of Willis to envelop the cerebral hemispheres. Smaller branches from the vertebral and basilar arteries distribute blood to the brainstem and cerebellum. The distributing arteries give rise to pial arteries that course over the surface of the brain, forming anastomoses, and then branch again into arterioles that penetrate the tissue at right angles to the brain surface. These penetrating arterioles branch centripetally to give rise to capillaries. The anastomoses on the cortical surface provide the collateral circulation that is so important should a distributing artery or one of its branches become occluded. Each of the four source arteries tends to supply the brain region closest to where the source artery joins the circle of Willis. If a stenosis develops in one source artery, other source arteries to the circle of Willis can provide alternative flow. Nevertheless, if flow through a carotid artery becomes severely restricted (e.g., with atherosclerotic plaque), ischemia may occur in the ipsilateral hemisphere, with impairment of function.
FIGURE 24-1 Vascular anatomy of the brain. The illustration in B, with the temporal lobe pulled away, depicts the major branches of the left middle cerebral artery, one of the distributing arteries. Pial arteries course over the surface of the brain and give rise to penetrating arterioles that supply the microcirculation within the brain.
The veins of the brain are wide, thin-walled structures that are nearly devoid of VSMCs and have no valves. In general, the veins drain the brain radially, in a centrifugal direction. The intracerebral veins converge into a superficial pial plexus lying under the arteries. The plexus drains into collecting veins, which course over the distributing arteries and empty into the dural sinuses (see Fig. 11-1B). The exception to this radial pattern is the deep white matter of the cerebral hemispheres and basal ganglia; these regions drain centrally into veins that course along the walls of the lateral ventricles to form a deep venous system, which also empties into the dural sinuses. Nearly all of the venous blood from the brain leaves the cranium by way of the internal jugular vein. N24-2
Contributed by Steve Segal
The emissary veins traverse the skull, carrying blood from the sinuses (e.g., superior sagittal sinus), which are surrounded by the dura mater inside the skull, to branches of the superficial temporal veins that are external to the skull. The emissary veins are typically responsible for little venous drainage from the brain.
One of the most characteristic features of the brain vasculature is the blood-brain barrier (see pp. 284–287), which prevents the solutes in the lumen of the capillaries from having direct access to the brain extracellular fluid (BECF). For this reason, many drugs that act on other organs or vascular beds have no effect on the brain. Polar and water-soluble compounds cross the blood-brain barrier slowly, and the ability of proteins to cross the barrier is extremely limited. Only water, O2, and CO2 (or other gases) can readily diffuse across the cerebral capillaries. Glucose crosses more slowly via facilitated diffusion. No substance is entirely excluded from the brain; the critical variable is the rate of transfer. The blood-brain barrier protects the brain from abrupt changes in the composition of arterial blood. In a similar manner, a blood-testis barrier protects the germinal epithelia in males. The blood-brain barrier may become damaged in regions of the brain that are injured, infected, or occupied by tumors. Such damage can be helpful in identifying the location of tumors because tracers that are excluded from healthy central nervous system (CNS) tissue can enter the tumor. In specialized areas of the brain—the circumventricular organs (see pp. 284–285)—the capillaries are fenestrated and have permeability characteristics similar to those of capillaries in the intestinal circulation.
The brain lacks lymphatic vessels.
The skull encloses all of the cerebral vasculature, along with the brain and the cerebrospinal fluid compartments. Because the rigid cranium has a fixed total volume, vasodilation and an increase in vascular volume in one region of the brain must be met by reciprocal volume changes elsewhere within the cranium. Precise control of the cerebral blood volume is essential for preventing elevation of the intracranial pressure. With cerebral edema or hemorrhage, or with the growth of a brain tumor, neurological dysfunction can result from the restriction of blood flow due to vascular compression. An analogous situation can occur in the eyes of patients with glaucoma (see pp. 360–361). Pressure buildup within the eye compresses the optic nerve and retinal artery, and blindness can result from the damage caused by diminished blood flow to the retinal cells.
Neural, metabolic, and myogenic mechanisms control blood flow to the brain
Cerebral blood flow averages 50 mL/min for each 100 g of brain tissue and, because of autoregulation, is relatively constant. Nevertheless, regional changes in blood distribution occur in response to changing patterns of neuronal activity (Fig. 24-2).
FIGURE 24-2 Changes in regional blood flow in the brain. The investigators used the washout of 133Xe (see p. 426), measured with detectors placed over the side of the patient's head, as an index of regional blood flow in the dominant cerebral hemisphere. The turquoise “hot spots” represent regions where blood flow is >20% above mean blood flow for the entire brain. At rest, blood flow is greatest in the frontal and premotor regions. The patterns of blood flow change in characteristic ways with the seven other forms of cerebral activity shown. (Data from Ingvar DH: Functional landscapes of the dominant hemisphere. Brain Res 107:181–197, 1976.)
Sympathetic nerve fibers supplying the brain vasculature originate from postganglionic neurons in the superior cervical ganglia and travel with the internal carotid and vertebral arteries into the skull, branching with the arterial supply. The sympathetic nerve terminals release norepinephrine, which causes contraction of VSMCs. Parasympathetic innervation of the cerebral vessels arises from branches of the facial nerve; these nerve fibers elicit a modest vasodilation when activated. The cerebral vessels are also supplied with sensory nerves, whose cell bodies are located in the trigeminal ganglia and whose sensory processes contain substance P and calcitonin gene–related peptide, both of which are vasodilatory neurotransmitters. Local perturbations (e.g., changes in pressure or chemistry) may stimulate the sensory nerve endings to release these vasodilators, an example of an axon reflex (see p. 571). N24-3
Contributed by George Richerson
Axon reflexes are thought to occur when a nerve ending is depolarized by local factors (e.g., irritation, pressure, seizures, altered pH, high [K+]o, or other chemical signals), triggering an action potential that travels anterograde along the axon to a branch point, where the action potential propagates back down another branch. Thus, an axon reflex is a local reflex arc that involves only the distal/peripheral part of a motor or sensory neuron.
In the case of a motor neuron, the stimulus would trigger an action potential that would move retrograde up the fiber to the branch point and then orthograde down to a terminal that would release its normal complement of neurotransmitters. Of course, when responding to its normal “central” stimuli, this motor neuron would function in the usual orthograde fashion.
In the case of a sensory fiber, the stimulus would travel orthograde along the axon to a branch point and then travel retrograde to other nerve endings. If these endings have release machinery, they could activate an effector. Varicosities on sensory fibers may contain substance P (SP) and calcitonin-gene–related peptide (CGRP), which the processes release in response to a local stimulus. Both SP and CGRP are vasodilatory neurotransmitters.
Another example of an afferent fiber that can release a neurotransmitter is the cranial nerve IX sensory neurons that innervate the glomus cells of the carotid body. As pointed out on pages 710–712, this is an example of a bidirectional synapse. The glomus cells can trigger an action potential in the sensory neuron, and the sensory neuron can apparently release neurotransmitters that may modulate the glomus cell.
Axon reflexes can also occur in neurons of the CNS—for example, from one part of the cortex to another.
Despite this innervation, neural control of the cerebral vasculature is relatively weak. Instead, it is the local metabolic requirements of the brain cells that primarily govern vasomotor activity in the brain.
Neural activity leads to ATP breakdown and to the local production and release of adenosine, a potent vasodilator. A local increase in brain metabolism also lowers while raising and lowering pH in the nearby BECF. These changes trigger vasodilation and thus a compensatory increase in blood flow. Cerebral VSMCs relax mainly in response to low extracellular pH; these cells are insensitive to increased per se, and decreased intracellular pH actually causes a weak vasoconstriction.
How does brain blood flow respond to systemic changes in pH? Lowering of arterial pH at a constant (metabolic acidosis; see p. 635) has little effect on cerebral blood flow because arterial H+ cannot easily penetrate the blood-brain barrier and therefore does not readily reach cerebral VSMCs. On the other hand, lowering of arterial pH by an increase in (respiratory acidosis; see p. 633) rapidly leads to a fall in the pH around VSMCs because CO2 readily crosses the blood-brain barrier. This fall in pH of the BECF evokes pronounced dilation of the cerebral vasculature, with an increase in blood flow that occurs within seconds. The rise in arterial caused by inhalation of 7% CO2 can cause cerebral blood flow to double. Conversely, the fall in arterial caused by hyperventilation raises the pH of the BECF, producing cerebral vasoconstriction, decreased blood flow, and dizziness. Clinically, hyperventilation is used to lower cerebral blood flow in the emergency treatment of acute cerebral edema and glaucoma.
A fall in the blood and tissue —from hypoxemia or impaired cardiac output—may also contribute to cerebral vasodilation, although the effects are less dramatic than those produced by arterial hypercapnia. The vasodilatory effects of hypoxia may be direct or may be mediated by release of adenosine, K+, or NO into the BECF. N24-4
Vasodilatory Effect of Hypoxia in the Brain
Contributed by Steve Segal, Emile Boulpaep, Walter Boron
A fall in the blood and tissue —from hypoxemia or impaired blood flow to the brain—may also contribute to vasodilation in the brain, although the effects are less dramatic than those produced by arterial hypercapnia. Several mediators may underlie the effect of hypoxia:
1. Adenosine. Levels of adenosine increase with hypoxia, reflecting the breakdown of ATP. Virtually any condition that increases brain O2 consumption will result in adenosine production and release within seconds. Because adenosine is a potent vasodilator (see Tables 20-8 and 20-9), increased adenosine levels tend to enhance blood flow and correct the hypoxia.
2. High [K+]. Hypoxia, seizures, and electrical stimulation all elevate [K+] in the BECF. Increased [K+]o leads to vasodilation (see Table 20-9; N24-6), which in turn tends to wash away the excess K+. Thus, elevated [K+]o may be involved only in the early portion of a hyperemic response.
3. NO. Both brain vascular endothelial cells and neurons contain nitric oxide synthase (see pp. 66–67 and 480) and thus can generate the highly permeable NO, which readily dilates the brain's resistance vessels.
4. Direct effects of low . A mechanism receiving increasing attention is the effect of O2 on the K+ conductance of the VSMC membrane: a fall in increases K+ conductance, promoting VSMC relaxation.
Cerebral resistance vessels are inherently responsive to changes in their transmural pressure. Increases in pressure lead to vasoconstriction, whereas decreases in pressure produce vasodilation.
The neurovascular unit matches blood flow to local brain activity
Neurons, glia, and cerebral blood vessels function as an integrated unit to distribute cerebral blood flow according to local activity within the brain (see Fig. 24-2). This “neurovascular coupling” involves several signaling pathways that complement the metabolic control discussed above. Some neurotransmitters and neuromodulators are vasoactive (e.g., acetylcholine, catecholamines, and neuropeptides) and can control blood vessels in the region of synaptic activity. The endfeet of astrocytes (see Fig. 11-6A) come into direct contact with the smooth muscle penetrating arterioles and the endothelial cells of capillaries. The release of neurotransmitters (e.g., glutamate and gamma-aminobutyric acid [GABA]) from neurons initiates [Ca2+]i waves in astrocytes as well as in dendrites of adjacent neurons. These [Ca2+]i waves stimulate the release of powerful vasodilators, including NO and metabolites of arachidonic acid. Thus, synaptic activity generates vasoactive mediators in neurons and astrocytes that can produce vasodilation. Concurrent activation of local interneurons with vascular projections helps to focus the vasomotor response. The vasodilator signal conducts through gap junctions from cell to cell along the endothelium and smooth-muscle cells of penetrating arterioles, retrograde to the pial arteries, which are a major part of vascular resistance. This reduction in proximal resistance directs increased blood flow to the region of increased neural activity.
Autoregulation maintains a fairly constant cerebral blood flow across a broad range of perfusion pressures
The perfusion pressure to the brain is the difference between the systemic arterial pressure (mean pressure, ~95 mm Hg) and intracranial venous pressure, which is nearly equal to the intracranial pressure (<10 mm Hg). A decrease in cerebral blood flow could thus result from a fall in arterial pressure or a rise in intracranial (or venous) pressure. However, the local control of cerebral blood flow maintains a nearly constant blood flow through perfusion pressures ranging from ~70 to 150 mm Hg. This constancy of blood flow—autoregulation (see p. 481)—maintains a continuous supply of O2 and nutrients. In patients with hypertension, the cerebral blood flow remains normal because cerebral vascular resistance increases. Conversely, vascular resistance falls with hypotension. This autoregulation of blood flow has both myogenic and metabolic components.
Increases in intracranial pressure compress the brain vasculature and tend to reduce blood flow despite autoregulatory vasodilation. In such cases, the brain regulates its blood flow by inducing reflexive changes in systemic arterial pressure. This principle is exemplified by the Cushing reflex, an increase in arterial pressure that occurs in response to an increase in intracranial pressure. It appears that intracranial compression causes a local ischemia that stimulates vasomotor centers in the medulla. Increased sympathetic nerve activity in the systemic circulation then triggers a rise in total peripheral resistance. The Cushing reflex may occur acutely with the swelling that follows a head injury or more gradually with growth of a brain tumor. Over a considerable pressure range, the Cushing reflex ensures that the perfusion pressure can offset the effects of vascular compression and thereby maintain the constancy of cerebral blood flow.