Comprehensive Physiology Wiley Online Library

Circulatory and Metabolic Correlates of Brain Function in Normal Humans

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Methods
1.1 Tracer Strategies
1.2 Instrumentation
1.3 Anatomical Localization Procedures
1.4 Statistical Considerations
2 Relationship of Neuronal Activity to Blood Flow and Energy Metabolism
2.1 Neuronal Function and Energy Metabolism
2.2 Blood Flow and Energy Metabolism
2.3 Effect of Elementary Stimulus Variables
3 Resting Awake Brain: Changes in Blood Flow and Metabolism
3.1 Normal Features
3.2 Sleep
3.3 Anxiety
3.4 Age
3.5 Anatomical Asymmetries and Atrophy
4 Activated Brain: Changes in Blood Flow and Metabolism
4.1 Voluntary Motor Activity
4.2 Somatosensory Stimulation
4.3 Visual Stimulation
4.4 Auditory Stimulation
4.5 Speech and Language
4.6 Mental Work
5 Conclusions
Figure 1. Figure 1.

Whole‐brain, inert‐gas (nitrous oxide) technique for the measurement of blood flow and metabolism in humans. Drawings depict experimental setup with needles in femoral artery and jugular bulb for measurement of arteriovenous differences across the brain, gas delivery system, and manifolds of syringes for sampling arterial and venous blood. This technique and tracer principles upon which it is based provided the basis for all subsequent tracer techniques for study of regional brain circulation and metabolism as well as fundamental data on circulation and metabolism of the human brain.

From Kety and Schmidt
Figure 2. Figure 2.

Geometry of regional nontomographic techniques for measurement of blood flow and metabolism in the human brain. Techniques are based on external detection of radioactive tracers administered by intracarotid or intravenous injection or by inhalation. Geometry of monitored region(s) of the brain depends on number and size of radiation detectors and on energy of tracer. Left: multidetector system with many small detectors; right: large single detector. Dark shadows extending as truncated cones from surface of detectors depict origin of data obtained with lower energy (81 keV) 133Xe (left) and much higher energy (511 keV) of 15O‐labeled radiopharmaceuticals (right). Multidetector systems with 133Xe are widely used in studies of regional brain blood flow in humans.

Figure 3. Figure 3.

Detection scheme for positron emission tomography (PET). Radionuclides employed in PET decay by emission of positrons (β+) from a nucleus unstable because of deficiency of neutrons. Positrons lose their kinetic energy in matter after traveling a finite distance (∼1–6 mm) and, when brought to rest, interact with electrons (β–). The 2 particles are annihilated, and their mass is converted to 2 annihilation photons traveling at ∼180° from each other with an energy of 511 keV. Annihilation photons are detected by imaging device, using opposing radiation detectors connected by electronic coincidence circuits that record an event only when 2 photons arrive simultaneously. A major factor determining the ultimate resolution of PET is distance traveled by positron before its annihilation.

From Raichle , reproduced with permission from the Annual Review of Neuroscience, © 1983 by Annual Reviews Inc
Figure 4. Figure 4.

Geometry employed in positron emission tomography. Multiple radiation detectors (type depicted in Fig. ) are arranged about subject's head and connected by coincidence circuits. Data from coincidence lines between detectors form quantitative image of distribution of radiopharmaceutical within the brain. Resulting image is equivalent to quantitative tissue autoradiogram obtained by exposing tissue containing radioactivity to X‐ray film. Spatial geometry of resulting image is very different from that obtained by multidetector, nontomographic systems (cf. Fig. ).

From Raichle
Figure 5. Figure 5.

Diagram of components of modern positron emission tomography system and ways in which data collection and formatting are performed. Data are collected in a list mode that records both the position of the radioactive event in the tissue and the time at which it occurs (i.e., instrument can record number of events occurring every 10 ms for period of time). Resulting image of distribution of radioactivity can be reconstructed either as 1) a single image representing sum of all radioactive decay events occurring during the study or 2) a sequence of images gated to a recurring electrical event in the brain such as cortical evoked response. Latter data format, not yet widely used for research on the brain, can relate circulatory events to brain electrical activity that is recurring over millisecond time intervals and may be important for future studies of brain functional activity.

Figure 6. Figure 6.

Diagram of concept of spatial resolution used in studies with positron emission tomography (PET). A: spatial resolution of PET system is operationally defined as width of an observed distribution of radioactive counts, produced by single point source of radioactivity in field of view of PET scanner, at 1/2 its maximum value (full width at half maximum or FWHM). B: when 2 point sources of radioactivity occur simultaneously in a PET image they cannot be distinguished from each other unless separated by at least 1 FWHM. C: 2 sequentially occurring point sources, however, can be distinguished from each other at considerably less than a distance of 1 FWHM. This fact has important implications for design and interpretation of future studies of functional activity in the human brain with PET.

Figure 7. Figure 7.

[14C]deoxyglucose autoradiographs and stained histological sections of coronal brain sections (left) and pituitary sections (right) in control and dehydrated rats demonstrating location of functionally induced changes in metabolism (i.e., neuropil vs. cell bodies). A: results characteristic of control rats, allowed to drink water freely. B: illustration of positions of the supraoptic (SON) and paraventricular (PVN) nuclei in brain section shown in A after cresyl violet (Nissl) staining. Positions of posterior pituitary (PP) and anterior pituitary (AP) are on the right in B after toluidine blue staining. C: autoradiography of brain and pituitary typical of dehydrated rats given 2% NaCl to drink for 5 days. Note intense labeling in PP without comparable change in SON and PVN, indicating good correlation between neuronal activity and deoxyglucose uptake in nerve terminals but no correlation in cell bodies of origin. D: results characteristic of normal rats after intravenous injection of α‐blocker (phenoxybenzamine) ∼1 h before injection of [14C]deoxyglucose. Note intense labeling in region of SON and PVN (presumably reflecting activity in afferent nerve terminals) as well as intense labeling in PP.

From Schwartz et al. . Copyright 1979 by the American Association for the Advancement of Science
Figure 8. Figure 8.

Local blood flow response measured with positron emission tomography in striate cortex of normal humans as function of stimulus repetition rate. Blood flow in striate cortex varied systematically with stimulus rate with maximum response at 7.8 Hz. Two stimuli (patterned flash and reversing checkerboard) were chosen to determine whether stimulus luminance or stimulus frequency was responsible for observed increases in striate cortex blood flow previously observed during photic stimulation . Regional cerebral blood flow (rCBF) changes are expressed as percent of change in rCBF from initial unstimulated scan. Each point represents mean rCBF % change from initial unstimulated scan. Error bars indicate ± 1 SE. Response curves show nearly identical rates despite other differences between the two stimulus modalities. Shape of blood flow response curves probably reflects relationships of type depicted in Fig. and underscores importance of understanding elementary stimulus variables in design of brain activation studies in experimental animals and in humans.

From Fox and Raichle
Figure 9. Figure 9.

Recordings of electrocorticogram (ECoG), local blood flow recorded with thermoelement (ThE) in cortical projection field of left forepaw in right sensorimotor cortex, systemic arterial blood pressure (SAP), and sensory evoked potential (EP) in cat under chloralose anesthesia during stimulation of left forepaw with 15‐V rectangular pulses 0.3 ms in duration. Output of stimulator (St) records stimulation time. Note relationship between EP and ThE. Changes in ThE do not appear until stimulus frequency reaches 3 Hz, reflecting the fact that average ThE during period of measurement is not appreciably affected at stimulation frequencies as low as 1 Hz. At stimulation frequencies >3 Hz in this particular system amplitude of EP and ThE decline in parallel.

K.‐A. Hossman, personal communication
Figure 10. Figure 10.

Summary of different regional cortical blood flow patterns obtained in normal human volunteers with regional nontomographic technique (see Fig. ) and 133Xe administered by intracarotid injection or inhalation. Absolute mean blood flow (value in box, in ml·min−1·100 g−1) for each hemisphere is shown along with percent increase in hemisphere blood flow during the test (value below box). Filled and empty circles indicate approximate location of regional flow measurements 20% above or below mean flow, respectively. Top left: composite diagram of 30 resting measurements in normal subjects (CONTROLS: REST). Note typical resting pattern obtained with this technique, described as hyperfrontal. Electrical cutaneous stimulation of the contralateral hand (e.g., right hand stimulated when blood flow measured in left hemisphere) with a low‐intensity stimulus (SENS 1) gives a pattern roughly similar to the high‐intensity stimulation (SENS 2). SENS 2, however, which was experienced as slight pain, increased mean hemisphere flow by 16%, possibly as result of anxiety. Failure of somatosensory stimulation to produce distinctive focal changes in blood flow may reflect improper selection of elementary stimulus variables as somatosensory stimulation in other studies have produced intense focal areas of activation . Voluntary hand movements give expected increases in the sensorimotor hand area along with an increase in hemisphere blood flow. Talking and reading produced two similar patterns at about the same resting blood flow. Finally, a reasoning test (i.e., oral description of geometric figures) and the serial subtraction of one number from another produced focal increases in blood in pre‐ and postcentral areas.

From Ingvar
Figure 11. Figure 11.

Positron emission tomographic (PET) image of local cerebral blood flow in a resting awake subject with panic disorder, a severe form of anxiety. Left half of image is a quantitative representation of cerebral blood flow corresponding to left side of the calibrated color scale. Right half of image represents the difference between right and left hemispheres expressed as percent of the left hemisphere blood flow in right half of the calibrated color scale. Image is oriented with subject's left at 9:00 and anterior at 12:00. Note striking asymmetry in posterior aspect of image. With a complex localization technique this regional asymmetry was determined to reside in region of the parahip‐pocampal gyrus. Other asymmetries appearing in image vary randomly among subjects.

From Reiman et al. . Reprinted by permission from Nature, copyright 1984, Macmillan Journal Limited
Figure 12. Figure 12.

Measurements of regional cerebral blood flow with non‐tomographic, intracarotid, 133Xe technique in normal subject at rest (bottom) and during mental operations on information retrieved from memory (top). Subject was asked to start with 50 and continuously subtract 3, silently. Subject was told to go on even if he reached negative numbers. He was not allowed to speak. Actual values for local blood flow (ml · min−1 · 100 g−1) from 254 regions sampled are shown on color scale to right of images. Approximate anatomical orientation of blood flow changes is indicated by outline of data on left cerebral hemisphere.

From Roland and Friberg


Figure 1.

Whole‐brain, inert‐gas (nitrous oxide) technique for the measurement of blood flow and metabolism in humans. Drawings depict experimental setup with needles in femoral artery and jugular bulb for measurement of arteriovenous differences across the brain, gas delivery system, and manifolds of syringes for sampling arterial and venous blood. This technique and tracer principles upon which it is based provided the basis for all subsequent tracer techniques for study of regional brain circulation and metabolism as well as fundamental data on circulation and metabolism of the human brain.

From Kety and Schmidt


Figure 2.

Geometry of regional nontomographic techniques for measurement of blood flow and metabolism in the human brain. Techniques are based on external detection of radioactive tracers administered by intracarotid or intravenous injection or by inhalation. Geometry of monitored region(s) of the brain depends on number and size of radiation detectors and on energy of tracer. Left: multidetector system with many small detectors; right: large single detector. Dark shadows extending as truncated cones from surface of detectors depict origin of data obtained with lower energy (81 keV) 133Xe (left) and much higher energy (511 keV) of 15O‐labeled radiopharmaceuticals (right). Multidetector systems with 133Xe are widely used in studies of regional brain blood flow in humans.



Figure 3.

Detection scheme for positron emission tomography (PET). Radionuclides employed in PET decay by emission of positrons (β+) from a nucleus unstable because of deficiency of neutrons. Positrons lose their kinetic energy in matter after traveling a finite distance (∼1–6 mm) and, when brought to rest, interact with electrons (β–). The 2 particles are annihilated, and their mass is converted to 2 annihilation photons traveling at ∼180° from each other with an energy of 511 keV. Annihilation photons are detected by imaging device, using opposing radiation detectors connected by electronic coincidence circuits that record an event only when 2 photons arrive simultaneously. A major factor determining the ultimate resolution of PET is distance traveled by positron before its annihilation.

From Raichle , reproduced with permission from the Annual Review of Neuroscience, © 1983 by Annual Reviews Inc


Figure 4.

Geometry employed in positron emission tomography. Multiple radiation detectors (type depicted in Fig. ) are arranged about subject's head and connected by coincidence circuits. Data from coincidence lines between detectors form quantitative image of distribution of radiopharmaceutical within the brain. Resulting image is equivalent to quantitative tissue autoradiogram obtained by exposing tissue containing radioactivity to X‐ray film. Spatial geometry of resulting image is very different from that obtained by multidetector, nontomographic systems (cf. Fig. ).

From Raichle


Figure 5.

Diagram of components of modern positron emission tomography system and ways in which data collection and formatting are performed. Data are collected in a list mode that records both the position of the radioactive event in the tissue and the time at which it occurs (i.e., instrument can record number of events occurring every 10 ms for period of time). Resulting image of distribution of radioactivity can be reconstructed either as 1) a single image representing sum of all radioactive decay events occurring during the study or 2) a sequence of images gated to a recurring electrical event in the brain such as cortical evoked response. Latter data format, not yet widely used for research on the brain, can relate circulatory events to brain electrical activity that is recurring over millisecond time intervals and may be important for future studies of brain functional activity.



Figure 6.

Diagram of concept of spatial resolution used in studies with positron emission tomography (PET). A: spatial resolution of PET system is operationally defined as width of an observed distribution of radioactive counts, produced by single point source of radioactivity in field of view of PET scanner, at 1/2 its maximum value (full width at half maximum or FWHM). B: when 2 point sources of radioactivity occur simultaneously in a PET image they cannot be distinguished from each other unless separated by at least 1 FWHM. C: 2 sequentially occurring point sources, however, can be distinguished from each other at considerably less than a distance of 1 FWHM. This fact has important implications for design and interpretation of future studies of functional activity in the human brain with PET.



Figure 7.

[14C]deoxyglucose autoradiographs and stained histological sections of coronal brain sections (left) and pituitary sections (right) in control and dehydrated rats demonstrating location of functionally induced changes in metabolism (i.e., neuropil vs. cell bodies). A: results characteristic of control rats, allowed to drink water freely. B: illustration of positions of the supraoptic (SON) and paraventricular (PVN) nuclei in brain section shown in A after cresyl violet (Nissl) staining. Positions of posterior pituitary (PP) and anterior pituitary (AP) are on the right in B after toluidine blue staining. C: autoradiography of brain and pituitary typical of dehydrated rats given 2% NaCl to drink for 5 days. Note intense labeling in PP without comparable change in SON and PVN, indicating good correlation between neuronal activity and deoxyglucose uptake in nerve terminals but no correlation in cell bodies of origin. D: results characteristic of normal rats after intravenous injection of α‐blocker (phenoxybenzamine) ∼1 h before injection of [14C]deoxyglucose. Note intense labeling in region of SON and PVN (presumably reflecting activity in afferent nerve terminals) as well as intense labeling in PP.

From Schwartz et al. . Copyright 1979 by the American Association for the Advancement of Science


Figure 8.

Local blood flow response measured with positron emission tomography in striate cortex of normal humans as function of stimulus repetition rate. Blood flow in striate cortex varied systematically with stimulus rate with maximum response at 7.8 Hz. Two stimuli (patterned flash and reversing checkerboard) were chosen to determine whether stimulus luminance or stimulus frequency was responsible for observed increases in striate cortex blood flow previously observed during photic stimulation . Regional cerebral blood flow (rCBF) changes are expressed as percent of change in rCBF from initial unstimulated scan. Each point represents mean rCBF % change from initial unstimulated scan. Error bars indicate ± 1 SE. Response curves show nearly identical rates despite other differences between the two stimulus modalities. Shape of blood flow response curves probably reflects relationships of type depicted in Fig. and underscores importance of understanding elementary stimulus variables in design of brain activation studies in experimental animals and in humans.

From Fox and Raichle


Figure 9.

Recordings of electrocorticogram (ECoG), local blood flow recorded with thermoelement (ThE) in cortical projection field of left forepaw in right sensorimotor cortex, systemic arterial blood pressure (SAP), and sensory evoked potential (EP) in cat under chloralose anesthesia during stimulation of left forepaw with 15‐V rectangular pulses 0.3 ms in duration. Output of stimulator (St) records stimulation time. Note relationship between EP and ThE. Changes in ThE do not appear until stimulus frequency reaches 3 Hz, reflecting the fact that average ThE during period of measurement is not appreciably affected at stimulation frequencies as low as 1 Hz. At stimulation frequencies >3 Hz in this particular system amplitude of EP and ThE decline in parallel.

K.‐A. Hossman, personal communication


Figure 10.

Summary of different regional cortical blood flow patterns obtained in normal human volunteers with regional nontomographic technique (see Fig. ) and 133Xe administered by intracarotid injection or inhalation. Absolute mean blood flow (value in box, in ml·min−1·100 g−1) for each hemisphere is shown along with percent increase in hemisphere blood flow during the test (value below box). Filled and empty circles indicate approximate location of regional flow measurements 20% above or below mean flow, respectively. Top left: composite diagram of 30 resting measurements in normal subjects (CONTROLS: REST). Note typical resting pattern obtained with this technique, described as hyperfrontal. Electrical cutaneous stimulation of the contralateral hand (e.g., right hand stimulated when blood flow measured in left hemisphere) with a low‐intensity stimulus (SENS 1) gives a pattern roughly similar to the high‐intensity stimulation (SENS 2). SENS 2, however, which was experienced as slight pain, increased mean hemisphere flow by 16%, possibly as result of anxiety. Failure of somatosensory stimulation to produce distinctive focal changes in blood flow may reflect improper selection of elementary stimulus variables as somatosensory stimulation in other studies have produced intense focal areas of activation . Voluntary hand movements give expected increases in the sensorimotor hand area along with an increase in hemisphere blood flow. Talking and reading produced two similar patterns at about the same resting blood flow. Finally, a reasoning test (i.e., oral description of geometric figures) and the serial subtraction of one number from another produced focal increases in blood in pre‐ and postcentral areas.

From Ingvar


Figure 11.

Positron emission tomographic (PET) image of local cerebral blood flow in a resting awake subject with panic disorder, a severe form of anxiety. Left half of image is a quantitative representation of cerebral blood flow corresponding to left side of the calibrated color scale. Right half of image represents the difference between right and left hemispheres expressed as percent of the left hemisphere blood flow in right half of the calibrated color scale. Image is oriented with subject's left at 9:00 and anterior at 12:00. Note striking asymmetry in posterior aspect of image. With a complex localization technique this regional asymmetry was determined to reside in region of the parahip‐pocampal gyrus. Other asymmetries appearing in image vary randomly among subjects.

From Reiman et al. . Reprinted by permission from Nature, copyright 1984, Macmillan Journal Limited


Figure 12.

Measurements of regional cerebral blood flow with non‐tomographic, intracarotid, 133Xe technique in normal subject at rest (bottom) and during mental operations on information retrieved from memory (top). Subject was asked to start with 50 and continuously subtract 3, silently. Subject was told to go on even if he reached negative numbers. He was not allowed to speak. Actual values for local blood flow (ml · min−1 · 100 g−1) from 254 regions sampled are shown on color scale to right of images. Approximate anatomical orientation of blood flow changes is indicated by outline of data on left cerebral hemisphere.

From Roland and Friberg
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Marcus E. Raichle. Circulatory and Metabolic Correlates of Brain Function in Normal Humans. Compr Physiol 2011, Supplement 5: Handbook of Physiology, The Nervous System, Higher Functions of the Brain: 643-674. First published in print 1987. doi: 10.1002/cphy.cp010516