Historical Review of Developments in the Field of Cerebral Blood Flow and Metabolism

Summary

Brain (cerebral) blood flow (CBF) and metabolism have long been subjects of great interest, but progress in their study awaited development of quantitative methods applicable to unanesthetized animals and man. The development of the nitrous oxide method by Kety and Schmidt (1948) revolutionized the field and led to much of our present knowledge of the physiology and pharmacology of CBF and energy metabolism in humans in health and disease. This method, however, measured only average CBF in the whole brain. This limitation was overcome by development of the autoradiographic [¹³¹I]trifluoroiodomethane (CF,¹³¹I) method by Kety and colleagues that measured local CBF simultaneously in all structures of the brain in conscious animals. Its autoradiograms provided visual images of the relative rates of CBF and led to the first demonstration of functional brain imaging (i.e., increases in CBF in structures of the cat visual system during retinal stimulation). The CF₃ ¹³¹I method was later modified for use with ¹⁴C autoradiography and a nonvolatile tracer, first[¹⁴C]antipyrine and then [¹⁴C]iodoantipyrine. This is the same method that was later adapted for use in humans with H₂ ¹⁵O and positron emission tomography (PET) and is now commonly used. The CF₃ ¹³¹I method and its derivatives were applied during uptake of tracer by cerebral tissues, but its basic principles apply equally well to clearance of the tracer from tissues. In 1949 Kety had reported a technique to determine local muscle blood flow by clearance of ²⁴Na injected into the tissue. This method was modified for use with radioactive gases, first ⁸⁵Kr and then ¹³³Xe, both of which freely cross the blood-brain barrier, and this clearance method has been used to measure regional CBF at rest and during alteration in local functional activity in humans. Energy metabolism is a function of individual cells, but CBF serves regions of the brain and is sensitive to systemic factors (e.g., blood gas tensions, pH). Measurement of local energy metabolism could therefore be expected to provide better resolution and specificity in response to altered neuronal functional activity. Sokoloff and coworkers, employing quantitative autoradiography together with radioactive 2-deoxy-n-glucose (2-DG), developed a method to measure local cerebral glucose utilization (1CMR_glc). They applied this method to localize and image local alterations in functional neuronal activity on the basis of changes in 1CMR_glc in many physiological, pharmacological, and pathological states and used it to define and quantify the relations between energy metabolism and functional and electrical activities in neural tissues. Because it employed autoradiography, the 2-DG method could not be used in humans. Therefore, Reivich and coworkers (1979) adapted the method for use in humans with Kuhl’s Mark IV single photon section scanner and the remitting analogue of 2-DG, 2-deoxy-2-[¹⁸F]fluoro-D-glucose ¹⁸FDG).¹⁸F is a positron emitter; and soon afterward Phelps, Kuhl, and coworkers (1979) modified the ¹⁸FDG method for use with PET with its superior spatial resolution and quantification. This method has been widely used to study regional energy metabolism in brain and other organs in humans in health and disease. Magnetic resonance imaging (MRI) techniques that provide signals correlating with changes in local CBF have recently been developed. These techniques measure increase in proton signal that occur when paramagnetic deoxyhemoglobin levels are reduced in the region of interest. Because CBF transiently increases more than O₂ consumption when brain tissue is activated, the venous deoxyhemoglobin content is reduced, and the enhancement in local proton signal is displayed in computer-generated reconstructed images. It should be noted that any cause of arterial vasodilatation, even if blood flow is not increased (e.g., during autoregulatory response to hypotension), reduces venous blood and deoxyhemoglobin contents in accordance with the principles of the Munro-Kellie doctrine. Nevertheless, MRIbased functional brain imaging has become the most popular CBF-related technique in use today because of its noninvasiveness, lack of ionizing radiation, excellent spatial and temporal resolution, and repeatability. Although it may correlate with changes in CBF, however, it does not measure it.