Cerebral Metabolism

The brain is metabolically one of the most actice of all organs in the body. The brain does not store excess energy and derives almost all of its energy needs from aerobic oxidation of glucose.  Therefore, it requires a continuous supply of glucose and oxygen to meet its energy requirements.  Most of the brain's energy consumption is used for active transport of ions to sustain and restore the membrane potentials discharged during the process of excitation and conduction.  When blood flow to the brain stops and absence of oxygen and blood occurs, a loss of consciousness results in 5-10 seconds.  If the blood flow is not resumed within several minutes, there is permanent brain damage.  It is well known that during crises, such as cardiac arrest, damage to the brain occurs earliest and is most decisive in determining the degree of recovery.  The absence of glucose is equally destructive, but the time course resulting in irreversible damage from hypoglycemia is longer because other substrates can be used.

Different regions of the brain have different energy requirements, which are related to the neuronal activity in these regions.  Measurement of amounts of glucose used per minute in different brain regions of a normal conscious rat and monkey demonstrates glucose utilization varies widely throughout the brain.  Moreover, the average value in the gray matter is approximately five times more than that in the white matter. 

The amount of blood flow is directly related to brain activity.  In a separate group of animals the amount of blood flow to brain areas was determined.  The results show that more blood flows to the area of the brain with high metabolic activity. 

Figure 11.10 shows there is an excellent correlation between the amount of glucose uses and local cerebral blood flow.  Regulation of blood flow to a brain area is achieved by control of dilation of cerebral vessels.  The dilation of blood vessels is controlled by local factors such as nitric oxide (NO), PaCO2, PaO2 and pH.  High NO, high PaCO2, low PaCO2  and low pH, which are produced as a result of brain activity, tend to dilate the blood vessels and increase blood flow.  The rate of production of these chemicals is dependent of activity and rates of energy metabolism.  Therefore, blood flow to a brain region is related to neuronal activity in that region.

Glucose utilization and brain imaging. Glucose metabolism is the major energy source for the brain. Glucose from the blood enters the brain with help of Glut-1 transport protein.  Once inside a brain cell, it enters the glycolytic pathway, where it is converted to pyruvate and then metabolized through the Kreb cycle to generate ATP.  A fraction of ATP molecules is used to generate high energy phosphocreatine molecules.  Under conditions, aerobic metabolism of glucose is capable of providing the brain with sufficient energy from ATP and phosphocreatine to maintain normal function.  When brain failure occurs, there is a loss of phosphocreatine initially, followed by ATP depletion, which generally signals severe damage to the brain. 

Glucose deprivation can result in abnormal brain function.  Hypoglycemia, which can result from excessive insulin, is associated with changes in mental state.  These changes can be rapidly reversed by glucose administration.   In certain circumstances, such as during starvation, the brain can use “ketone bodies” in place of glucose as substrates.  Ketone bodies, acotacetate and D-beta-hydroxybutyrate are formed from catabolism of fatty acids by the liver.  The ketone bodies are metabolized to generate

acyl-CoA which enters the tricarboxylic acid cycle (TCA) at a sufficient rate to meet the metabolic demand of the brain. 

Measurement of local glucose utilization.  The local energy metabolism is coupled to local functional activity.  Using an autoradiography analog of glucose, 2-deoxyglucose (2-DG), has been employed to measure glucose metabolism in experimental animals. 

Figure 11.4 illustrates the fundamental principle of radioactive deoxy glucose method for measuring the local cerebral glucose utilization.  Glucose utilization begins with phosphorylation of glucose by hexokinase.  The resulting glucose-6-phosphate is not retained in the tissues.  Instead, it is metabolized further to products such as CO2 and H2O that leave the tissue.  2-deoxyglucose is an analog of glucose and is transported across the blood-brain barrier by the glucose carrier system.  Inside brain cells, 2-deoxyglucose is phosphorylated by hexokinase to deoxyglucose-6-phosphate (DG-6-P) and cannot be further degraded into CO2 and H2O.  Instead it is trapped and accumulates in the tissue quantitatively for a reasonable length of time.  By putting a label on deoxyglucose (such as in [18F] fluoro-2-deoxy-D-glucose), it is possible to measure the rate of labeled deoxyglucose-6-phosphate formation.  The amount of 18FDG-6-phosphate can be directly determined using positron emission tomography (PET).  The 2-deoxyglucose method has been modified for human use with PET, with short lived positron emitting isotopes labeled to the 2-deoxyglucose.

11.6 Functional Activation of Energy Metabolism

Because of the coupling of metabolism to function, functional activation by specific stimuli tasks leads to regional increase in the glucose metabolism in corresponding cerebral structures.  Movement of fingers and hands increases metabolism in the respective brain regions.  In right handed volunteers, spontaneous speech increased metabolic activities in Broca's region.  Presentation of visual images increases glucose utilization in the primary visual cortex.

Functional MRI. A variant of MRI called functional MRI (fMRI) is based on the increase in the blood flow to specific brain regions that accompanies neuronal activity.  Increase in blood flow results in a local decrease in deoxyhemoglobin due to less oxygen extraction.   Deoxyhemoglobin is paramagnetic and serves as the source for the signal in fMRI.  Unlike PET, fMRI uses a signal intrinsic to the brain and has emerged as the technology of choice for probing brain function. 

            11.7 Brain Disorders and Metabolism

Convulsive disorders are functional disturbances of brain activity and lead to marked changes in brain metabolism and cerebral blood flow.  The metabolic changes detected by PET can frequently complement electrophysiological recordings to locate epileptogenic foci.  This information helps neurosurgeons to surgically remove the epileptogenic focus.

Metabolic measurements using PET can be used to determine the size of infarction following ischemic stroke.  Brain tumors have high metabolic needs and are heavily

vascularized.  PET or fMRI can be used to locate the tumor and evaluate effectiveness of a therapy.