Normal blood flow through the brain of the adult person averages 50 to 65 milliliters per 100 grams of brain tissue per minute. For the entire brain, this amounts to 750 to 900 ml/min. Thus, the brain constitutes only about 2 percent of the body weight but receives 15 percent of the resting cardiac output.
As in most other tissues, cerebral blood flow is highly related to the tissue metabolism. Several metabolic factors are believed to contribute to cerebral blood flow regulation: (1) carbon dioxide concentration, (2) hydrogen ion concentration, (3) oxygen concentration, and (4) sub stances released from astrocytes, which are specialized, non-neuronal cells that appear to couple neuronal activity with local blood flow regulation.
Excesses of Carbon Dioxide or Hydrogen Ion Concentration Increase Cerebral Blood Flow. An increase in carbon dioxide concentration in the arterial blood perfusing the brain greatly increases cerebral blood flow. This is demonstrated in Figure 1, which shows that a 70 percent increase in arterial partial pressure of carbon dioxide (PCO2) approximately doubles cerebral blood flow.
Fig1. Relationship between arterial PCO2 and cerebral blood flow.
Carbon dioxide is believed to increase cerebral blood flow by combining first with water in the body fluids to form carbonic acid, with subsequent dissociation of this acid to form hydrogen ions. The hydrogen ions then cause vasodilation of the cerebral vessels, with the dilation being almost directly proportional to the increase in hydrogen ion concentration up to a blood flow limit of about twice normal.
Other substances that increase the acidity of the brain tissue and therefore increase hydrogen ion concentration will likewise increase cerebral blood flow. Such substances include lactic acid, pyruvic acid, and any other acidic material formed during the course of tissue metabolism.
Importance of Cerebral Blood Flow Control by Carbon Dioxide and Hydrogen Ions. Increased hydrogen ion concentration greatly depresses neuronal activity. Therefore, it is fortunate that increased hydrogen ion concentration also causes increased blood flow, which in turn carries hydrogen ions, carbon dioxide, and other acid forming substances away from the brain tissues. Loss of carbon dioxide removes carbonic acid from the tissues; this action, along with removal of other acids, reduces the hydrogen ion concentration back toward normal. Thus, this mechanism helps maintain a constant hydrogen ion concentration in the cerebral fluids and thereby helps to maintain a normal, constant level of neuronal activity.
Oxygen Deficiency as a Regulator of Cerebral Blood Flow. Except during periods of intense brain activity, the rate of oxygen utilization by the brain tissue remains within narrow limits—almost exactly 3.5 (±0.2) milliliters of oxygen per 100 grams of brain tissue per minute. If blood flow to the brain ever becomes insufficient to supply this needed amount of oxygen, the oxygen deficiency almost immediately causes vasodilation, returning the brain blood flow and transport of oxygen to the cerebral tissues to near normal. Thus, this local blood flow regulatory mechanism is almost exactly the same in the brain as in coronary blood vessels, in skeletal muscle, and in most other circulatory areas of the body.
Experiments have shown that a decrease in cerebral tissue partial pressure of oxygen (PO2) below about 30 mm Hg (the normal value is 35 to 40 mm Hg) immediately begins to increase cerebral blood flow. This is fortuitous because brain function becomes deranged at lower values of PO2, especially at PO2 levels below 20 mm Hg. Even coma can result at these low levels. Thus, the oxygen mechanism for local regulation of cerebral blood flow is an important protective response against diminished cerebral neuronal activity and, therefore, against derangement of mental capability.
Substances Released from Astrocytes Regulate Cerebral Blood Flow. Increasing evidence suggests that the close coupling between neuronal activity and cerebral blood flow is due, in part, to substances released from astrocytes (also called astroglial cells) that surround blood vessels of the central nervous system. Astrocytes are star shaped non-neuronal cells that support and protect neurons, as well as provide nutrition. They have numerous projections that make contact with neurons and the sur rounding blood vessels, providing a potential mechanism for neurovascular communication. Gray matter astrocytes (protoplasmic astrocytes) extend fine processes that cover most synapses and large foot processes that are closely apposed to the vascular wall (see Figure 2).
Fig2. Architecture of cerebral blood vessels and potential mechanism for blood flow regulation by astrocytes. The pial arteries lie on the glia limitans, and the penetrating arteries are surrounded by astrocyte foot processes. Note that the astrocytes also have fine processes that are closely associated with synapses.
Experimental studies have shown that electrical stimulation of excitatory glutaminergic neurons leads to increases in intracellular calcium ion concentration in astrocyte foot processes and vasodilation of nearby arterioles. Additional studies have suggested that the vasodilation is mediated by several vasoactive metabolites released from astrocytes. Although the precise mediators are still unclear, nitric oxide, metabolites of arachidonic acid, potassium ions, adenosine, and other substances generated by astrocytes in response to stimulation of adjacent excitatory neurons have all been suggested to be important in mediating local vasodilation.
Measurement of Cerebral Blood Flow and Effect of Brain Activity on Flow. A method has been developed to record blood flow in as many as 256 isolated segments of the human cerebral cortex simultaneously. To record blood flow in these segments, a radioactive substance, such as radioactive xenon, is injected into the carotid artery; then the radioactivity of each segment of the cortex is recorded as the radioactive substance passes through the brain tissue. For this purpose, 256 small radioactive scintillation detectors are pressed against the surface of the cortex. The rapidity of rise and decay of radioactivity in each tissue segment is a direct measure of the rate of blood flow through that segment.
Using this technique, it has become clear that blood flow in each individual segment of the brain changes as much as 100 to 150 percent within seconds in response to changes in local neuronal activity. For instance, simply making a fist of the hand causes an immediate increase in blood flow in the motor cortex of the opposite side of the brain. Reading a book increases the blood flow, especially in the visual areas of the occipital cortex and in the language perception areas of the temporal cortex. This measuring procedure can also be used for localizing the origin of epileptic attacks because local brain blood flow increases acutely and markedly at the focal point of each attack.
Figure 3 demonstrates the effect of local neuronal activity on cerebral blood flow by showing a typical increase in occipital blood flow recorded in a cat’s brain when intense light is shined into its eyes for one-half minute.
Fig3. Increase in blood flow to the occipital regions of a cat’s brain when light is shined into its eyes.
Blood flow and neural activity in different regions of the brain can also be assessed indirectly by functional magnetic resonance imaging (fMRI). This method is based on the observation that oxygen-rich hemoglobin (oxyhemoglobin) and oxygen-poor hemoglobin (deoxyhemoglobin) in the blood behave differently in a magnetic field. Deoxyhemoglobin is a paramagnetic molecule (i.e., attracted by an externally applied magnetic field), whereas oxyhemoglobin is diamagnetic (i.e., repelled by a magnetic field). The presence of deoxyhemoglobin in a blood vessel causes a measurable difference of the magnetic resonance (MR) proton signal of the vessel and its surrounding tissue. The blood oxygen level–dependent (BOLD) signals obtained from fMRI, however, depend on the total amount of deoxyhemoglobin in the specific three-dimensional space (voxel) of brain tissue being assessed; this, in turn, is influenced by the rate of blood flow, volume of blood, and rate of oxygen consumption in the specific voxel of brain tissue. For this reason, BOLD fMRI provides only an indirect estimate of regional blood flow, although it can also be used to produce maps showing which parts of the brain are activated in a particular mental process.
An alternative MRI method called arterial spin labeling (ASL) can be used to provide a more quantitative assessment of regional blood flow. ASL works by manipulating the MR signal of arterial blood before it is delivered to different areas of the brain. By subtracting two images in which the arterial blood is manipulated differently, the static proton signal in the rest of the tissue subtracts out, leaving only the signal arising from the delivered arterial blood. ASL and BOLD imaging can be used together to provide simultaneously a probe of regional brain blood flow and neuronal function.
Cerebral Blood Flow Autoregulation Protects the Brain From Fluctuations in Arterial Pressure Changes. During normal daily activities, arterial pressure can fluctuate widely, rising to high levels during states of excitement or strenuous activity and falling to low levels during sleep. However, cerebral blood flow is “autoregulated” extremely well between arterial pressure limits of 60 and 140 mm Hg. That is, mean arterial pressure can be decreased acutely to as low as 60 mm Hg or increased to as high as 140 mm Hg without significant change in cerebral blood flow. In addition, in people who have hypertension, autoregulation of cerebral blood flow occurs even when the mean arterial pressure rises to as high as 160 to 180 mm Hg. This is demonstrated in Figure 4, which shows cerebral blood flow measured in both persons with normal blood pressure and in hypertensive and hypotensive patients. Note the extreme constancy of cerebral blood flow between the limits of 60 and 180 mm Hg mean arterial pressure. However, if the arterial pressure falls below 60 mm Hg, cerebral blood flow becomes severely decreased.
Fig4. Effect of differences in mean arterial pressure, from hypotensive to hypertensive level, on cerebral blood flow in different human beings. (Modified from Lassen NA: Cerebral blood flow and oxygen consumption in man. Physiol Rev 39:183, 1959.)
Role of the Sympathetic Nervous System in Controlling Cerebral Blood Flow. The cerebral circulatory system has strong sympathetic innervation that passes upward from the superior cervical sympathetic ganglia in the neck and then into the brain along with the cerebral arteries. This innervation supplies both the large brain arteries and the arteries that penetrate into the substance of the brain. However, transection of the sympathetic nerves or mild to moderate stimulation of them usually causes little change in cerebral blood flow because the blood flow autoregulation mechanism can override the nervous effects.
When mean arterial pressure rises acutely to an exceptionally high level, such as during strenuous exercise or during other states of excessive circulatory activity, the sympathetic nervous system normally constricts the large- and intermediate-sized brain arteries enough to prevent the high pressure from reaching the smaller brain blood vessels. This mechanism is important in preventing vascular hemorrhages into the brain—that is, for preventing the occurrence of “cerebral stroke.”
