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PEDIATRICS (ISSN 0031 4005). Copyright © 1982 by the
American Academy of Pediatrics.
650 PEDIATRICS Vol. 70 No. 4 October 1982
7. Laurence KM, James N, Campbell H: Quality of the diet and blood folate levels. Br Med J 285:216, 1982
8. Hibbard ED, Smithells RW: Folic acid metabolism and
human embryopathy. Lancet 1:1254, 1965
9. Laurence KM, James N, Miller M, et al: Double-blind ran-domised controlled trial of folate treatment before concep-tion to prevent recurrences of neural tube defects. Br Med
J282:1511, 1981
10. Laurence KM, Campbell H: Trial of folate treatment to prevent recurrence of neural tube defect. Br Med J 282:2131,
1981
11. Stone D: Possible prevention of neural tube defects by periconceptional vitamin supplementation. Lancet 1:647,
1980
12. Smithells RW, Sheppard 5, Schorah CJ: Trial of folate
therapy to prevent recurrences of neural tube defects. Br
Med J 282:1793, 1981
13. Seller MJ: Nutritional supplementation and prevention of
neural tube defects, in Hoots E, Wiley AM (eds): Clinical
Genetics: Problems in Diagnosis and Counselling. New
York, Academic Press, in press 1982
Pathophysiology,
Live
In the August issue of Pediatrics, Delpy et al’ provided a detailed description of changes in
intra-cerebral, intracellular constituents before, during,
and after severe ischemic events in rabbits using a nuclear magnetic resonance technique. The constit-uents, ATP, phosphocreatine (PCr), and sugar phosphates, are the basic energy substrates of the
body. Intracellular pH was also monitored through-out. As the authors correctly point out, such non-invasive, in vivo biochemistry would be invaluable to the pediatric clinician, not only to gather direct metabolic information on the status of the brain, but also to increase knowledge about muscle.2 In
fact, applications of this technique to other organs such as the liver,3 the kidney,4 and the heart5 are likely to be made soon. With the advent of nonin-vasive biochemical observation by this means, a radical increase in our clinical diagnostic power may be in the offing.
Spatially localized, high resolution nuclear
mag-netic resonance (NMR) spectroscopy, allowing in-sight into the biochemistry of the working brain and other organs, is new to clinical medicine.
How-ever, NMR spectroscopy has long been used for “test tube” chemistry. It takes advantage of the fact that the nuclei of many naturally occurring, non-radiative stable atoms generate small magnetic fields. Each such nucleus can be thought of as a tiny magnet, with its poles susceptible to
orienta-tion in any stronger magnetic field. Once the mag-netic nuclei are oriented by a strong fixed magnetic field, the addition of a second magnetic influence, oriented at a different angle, will pull the atomic magnets away from the fixed orientation. If the second magnetic influence is then turned off, the nuclei will return to their original orientation in the fixed magnetic field, creating a detectable radio-frequency signal. The greater the concentration of such atoms, the stronger will be the signal they generate.
It is important to note that the energies involved in these magnetic orientation processes are negli-gible compared with those involved in, for instance, ionizing radiation. Conventional x-rays, with their high amounts of energy, can disrupt biologic proc-eases by breaking chemical bonds, causing irrevers-ible changes in molecules. NMR processes are at such a low energy level that they have no effect on chemical activity. From this flows a major advan-tage of high resolution NMR-detrimental biologic “side effects” do not occur, as far as is known to date. It also leads to a limitation, namely that substantial concentrations of a given magnetic nu-elide must be present to produce a detectable NMR signal. Each of the nuclides with magnetic proper-ties (some common ones are H-i, C-13, N-14, N-15, F-19, P-31, Na-23, K-39, Ca-43) produces and re-sponds to a particular radiofrequency at a given
magnetic
field
strength. The molecular environ-ments of the atoms change the characteristic fre-quency slightly, uniquely, and reproducibly for each molecule. This is called the “chemical shift” phe-nomenon, ie, the characteristic change produced by the molecular environment (ie, the circulation of electrons) about a magnetic nuclide. It allows posi-tive identffication of different molecules that con-tam a given magnetic nuclide. Hence, in the Delpy et al article,’ phosphocreatine (PCr) is visualized as distinct from sugar phosphate. Likewise, each of the three phosphates in ATP appears as a separate peak, since each experiences a unique chemical environment. Different concentrations of W ions also affect the chemical shift of some molecules (eg,inorganic
phosphate) but not others (eg, PCr) and this allows a determination of pH by NMR. As the PCr and Pi are intracellular, intracellular pH is determined.The advent of in vivo high resolution NMR into the clinical arena is being facilitated by the surface coil antenna.6 This device allows for fully noninva-sive biochemical study of in vivo tissue. Essentially the surface coil (SC) is a transmitter, for applying the appropriate magnetic force to cause the mag-netic nuclei to deviate out of the orientation of the fixed magnetic field. It is also a receiver, for detect-ing the frequency generated by the magnetic ions
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COMMENTARIES 651
as they return to their original orientation after cessation of the second magnetic field. In conven-tional NMR, to ensure maximum signal to noise, this transmitter-receiver surrounds the sample. The first major advantage of the SC, however, is that it may simply be placed over the tissue to be moni-tored. A second major advantage of the SC is that
it allows for localization of the NMR signal. The area from which the NMR signal is detected is
determined by the geometry of the SC. The
local-izing properties of the SC have been little exploited to date, however, there wifi clearly be
improve-ments in the mapping capabilities of high resolution
NMR spectroscopy as time goes on. Already addi-tional, more complex spatial resolution procedures have been designed and used with SC antennae. SC-NMR capability for monitoring internal meta-bolic events over the course of hours without so much as a venipuncture will likely prove clinically invaluable, as suggested by the index article. Even more useful, especially in pediatrics, is the potential for repeated SC-NMR monitoring periods. Thus, long-term noninvasive investigations of biochemical parameters of growth and development7 may be achieved.
SC-NMR spectroscopy must be distinguished from NMR imaging, an application of NMR that is already well established on the clinical scene. NMR imaging, developed in large part by the efforts of
Lauterbur,8 utilizes the very strong radio-frequency signals produced by hydrogen (H-i). The body con-tains plenty of hydrogen (for instance in water and fat), but in varying concentrations in different tis-sues. The organ-to-organ variation in hydrogen con-centration allows the construction of images. Al-though it provides some limited physiologic infor-mation, NMR imaging is currently similar to com-puted tomography (CT) scanning with conventional x-ray, yielding primarily structural information. It is being exploited especially for the beautiful clarity of the images it produces, as soft tissue contrast is considerably greater than in CT scans. It is easy to obtain NMR data in such a way that images can be
reconstructed in virtually any plane, and no ionizing
radiation whatsoever is involved. The spatial reso-lution of NMR imaging is good. Development of “magnetic tracer” techniques may allow more dy-namic, physiologic information to be obtained. An extensive review of NMR imaging is available.9 Combinations of spectroscopy with imaging and magnetic focusing methods hold great promise for
the future.
A second new technique that allows observation of ongoing physiologic processes in situ and in vivo is positron emission tomography (PET). It is far more advanced in clinical application than NMR. It utilizes the property of selected radioactive
iso-topes to emit positrons. Positrons collide with elec-trons from tissue shortly after emission. At this
collision, the two particles are annihilated and their
energy is released as two photons which travel at a given speed and angle (180#{176})away from the site of
the annihilation. Photons are detected simultane-ously by receivers 180#{176}apart, thus pinpointing the location of the source, and providing the spatial
information from which the image is constructed.
Depending upon the emitting isotope used, and the substance to which it is attached, quantitative im-ages of various physiologic processes, such as tissue blood flow, oxygen utilization, glucose utilization,
and protein synthesis may be made. PET in some measure combines the advantages of NMR spec-troscopy and imaging, as it yields both images and physiologic information together. Raichle’#{176} had made a comprehensive review of PET techniques.
While still developing rapidly, some form of PET has been in use for a number of years. It has already revealed many new clinical facts that are both in consonance with, and at odds with, traditional in-formation. For example, a major clinical use has been in evaluation of individuals with strokes and other circulatory cerebral disturbances.” The use of PET to study newborns with intraparenchymal hemorrhage, originally demonstrated by traditional structural imaging techniques (CT and echoenceph-alography) has revealed reduced blood flow in
ex-tensive areas of the damaged hemisphere.’2 In this instance the physiologic measure suggests a much wider distribution of defect than was revealed by other studies. Cerebral glucose utilization has been studied in patients with cortical function deficits and epilepsy. Again, information not available from traditional methods has come to light: CT scans may demonstrate intact structure and the PET
scan shows pathologic glucose utilization. In aphas-ics, for example, glucose utilization is diminished not only in cortex but also in subcortical thalamic
structures.’3 In epileptic children and young adults, during a seizure the cerebral focus (as determined by clinical symptoms and EEG determinations) uses glucose at a greatly accelerated rate, but be-tween seizures, the same region of brain shows severely depressed glucose utilization.’4 This latter
finding lends new insight to the clinician, and also provides a new method for finding foci interictaily.
Although PET scanning allows relatively nonin-vasive evaluation of certain pathophysiologic events, it has limitations. One is the need for the introduction of radiopharmaceuticals. PET scan-ning has, to date, been little utilized in children primarily due to radiation safety considerations. This problem is being minimized by careful phar-macologic engineering and more sophisticated, more rapid, scanning. A second drawback of PET
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652 PEDIATRICS Vol. 70 No. 4 October 1982
is the requirement that heavy equipment for flu-clear bombardment be close to the PET scanner and the need for rapid synthesis of radiopharma-ceuticals. Medical centers with such facilities are limited in number. A third disadvantage of PET is
that the actual scan captures only one time point in a physiologic process. Monitoring, so readily carried out with NMR, would be extremely cumbersome with PET. Theoretically, spatial resolution is also a limitation; however, so much new physiologic
information being acquired, the current spatial
res-olution of most PET scanners, 15 mm, hampers only some of its applications. To date, major ad-vances have been made by the use of PET. As successful solving of the problems of practical ap-plication continues, more clinically relevant facts
will be forthcoming.
NMR spectroscopy and imaging, and PET
scan-ning are at a different stages of development for clinical application. Together, however, these tech-niques put us at the threshold of a new era. In this new era we can hope to answer questions concern-ing normal and pathologic human physiology and biochemistry, especially during development, that could not be addressed even five years ago. For the first time we have the means to observe biochem-istry and physiology in situ as they happen without harm to the subject or even appreciable alteration
of the ongoing processes under observation by the instrument of observation. These methods will be particularly beneficial in the study of the neonate in whom normal developmental processes imply a
background of rapidly changing physiology. For neonatology, as for all of medicine, such nonde-structive, noninvasive methods are ideal.
RUTHMARY K. DEUEL, MD
Edward M. Maffinckrodt Department of Pediatrics and
McDonnell Center for Higher Cortical Functions
Washington University School of Medicine
St Louis
REFERENCES
1. Delpy DT, Gordon RE, Hope PL, et al: Noninvasive
inves-tigation of cerebral ischemia by phosphorus. Pediatrics 70:310, 1982
2. Ross B, Radda G, Gadian D, et al: Examination of a case of suspected McArdle’s syndrome by P-31 NMR. N Engi J
Med304:1338, 1981
3. Chan L, Waterton J, Radda G: A study of rat kidney in vivo
during hypovolaemic shock by P-31 NMR. Biochem Soc Trans 9:239, 1981
4. McLaughlin A, Taheda H, Chance B: Rapid ATP assays in perfused mouse liver by P-31 NMR. Proc Nati Acad Sci
USA 76:5445, 1979
5. Ackerman J, Bore P, Gadian D, et a!: NMR studies of metabolism in perfused organs. Philos Trans R Soc Lond [Biol] 289:425, 1980
6. Ackerman J, Grove G, Wong G, et al: Mapping of metabol-ytes in whole animals by P-31 NMR using surface coils. Nature 283:167, 1980
7. Yue G, Ackerman J, Deuel R: Monitoring cerebral activity by surface Coil NMR, abstract, ed. Ann Neurol 10:291, 1981 8. Lauterbur P, Kramer D, House W Jr, et al: Zeugmatographic
high resolution nuclear magnetic resonance spectrosopy:
Images of chemical inhomogeneity within macroscopic
ob-jects. J Am Chem Soc 97:6866, 1975
9. Pykett I: NMR imaging in medicine. Sci Am 246:78, 1982
10. Raichle M: Quantitative in vivo autoradiography with
posi-tron emission tomography. Brain Res Rev 1:47, 1979
11. Raichle M, Markham J, Larson K, et al: Measurement of
local cerebral blood flow in man with positron emission tomography. Sixth Joint Meeting on Stroke and Cerebral
Circulation, Los Angeles, Feb 12-14, 1981. Stroke 12:121, 1981
12. Volpe J, Perlman J, et al: Positron emission tomography
(PET) in the assessment of regional cerebral blood flow in the newborn. Ann Neurol 12:195, 1982
13. Metter E, Wasterlain C, Kuhl D, et al: 18FDG positron emission computed tomography in a study’#{231}f aphasia. Ann
Neurol 10:173, 1981
14. Kuhl D, Engel J, Phelps M, et al: Epileptic patterns of local cerebral metabolism and perfusion in humans determined by emission computed tomography of 18FDG and 13NH3. Ann Neurol 8:348, 1980
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1982;70;650
Pediatrics
Ruthmary K. Deuel
Pathophysiology, Live
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