B rain development in mostspecies, including humans,is characterized by both

overgrowth and elimination phases.This general phenomenon applies toneuronal populations as well as totheir processes and synaptic contacts. Whereas the proliferation andoverproduction of neurons in humans occur prenatally, the elimination phase of excessively proliferated neuronal populations beginsprenatally and continues until aboutthe second postnatal year (1). Onthe other hand, the overproductionand subsequent elimination (also referred to as “pruning―)of neuronalprocesses and their synaptic contacts in man is largely a postnatalphenomenon with a rather protracted course. Indeed, synapticconcentrations in both human frontal (2) and visual (3) cortices ofchildren up to 11 yr of age havebeen shown to exceed those of corresponding regions in adults bynearly a factor of two, despite thefact that adult size and weight of thebrain has already been reached bythis age. The process of transientexuberant connectivity as a generalrule in brain development acrossmany species is believed to be biologically advantageous in reducingthe genetic burden that would otherwise be required for specificallyprogramming the enormous numbers of synaptic contacts (on theorder of l0'@in humans) in the central nervous system (4,5).

Postnatal development ofthe human brain, therefore, is an incredibly dynamic process. The full-termmale newborn has an average brainweight of 370 g, which triples to

ReceivedSept. 12, 1990;acceptedSept. 12,1990.For reprintscontact: HarryT. Chugani,MD,Division of PedsathCNeurology,Room 22.464MDCC,uc@ Schoolof Medicine,Los Angeles,CA90024.

LCMRG1cin well over 100 infantsand children. Each had been justifled to undergo FDG-PET becauseof its potential to contribute to theclinical management of the infantor child. We then selected 29 subjects, who in retrospect, had eithersuffered only transient neurologicevents not affecting development orhad neurologic disease ruled out altogether. We believed that this subpopulation was adequately representative of normal children to provide an initial description ofLCMRGIc ontogeny.

Using this strategy, we found thepauern of LCMRG1c in the humanneonate to be markedly differentfrom that of the adult; typically,four brain regions visualized onPET are metabolically prominent innewborns: primary sensonmotorcortex, thalamus, brainstem, andcerebellar vermis. Phylogenetically,these are relatively old structures,which dominate the behavior andparticipate in the primitive intrinsicreflexes ofthe normal newborn.

During the first year, the ontogeny of glucose metabolic patternsproceeds in phylogenetic order, withfunctional maturation of older anatomic structures preceding that ofnewer areas (9). This sequenceoffunctional developmental correlated well with the behavioral, neurophysiologic, and neuroanatomicmaturation of the infant. As the infantacquiresvisuo-spatialand visuosensorimotor integrative functionsin the second and third months oflife, and primitive reflexes becomesuppressed, increases in LCMRG1care observed in parietal, temporaland primary visual cortical regions,basal ganglia, and cerebellar hemispheres. The last region to undergoa maturational rise in LCMRG1c isthe frontal cortex, where maturationof the lateral portion precedes that

1080 g by 3 yr. By 6—14 yr, theaverage brain weight is 1350 g. Theprocesses of dendritic and synapticproliferation, together with theirmaintenance, myelination, and various other synthetic processes in thepostnatally developing brain undoubtedly demand a great deal ofprotein synthesis and energy expenditure for their construction andfunction. Kennedy and Sokoloff(6), in their pioneering studies usingthe nitrous oxide method, demonstrated that the average global cerebral blood flow in children betweenthe ages of 3 and 11 yr exceededaverage adult values by a factor of1.8. Average global brain oxygenutilization similarly exceeded adultrates by a factor of 1.3. Since thesewerewholebrain measurements,local areas of the brain may have exhibited much higher rates.

Due to the developmentof positron emission tomography (PET)(7),a numberofbiochemicandbiologic processes in the maturingbrain can now be directly imagedand measured in vivo noninvasively(8). With regard to the applicationof PET in childhood, one is confronted with a dilemma. Ontogenetic changes of various measurements obtained with PET in thenormally developing brain mustfirst be established prior to applyingPET to the study of childhood disease. It is, however, unethical andunacceptable to perform PET studies on entirely normal children forpurely research purposes. Variousstrategies must, therefore, be employed in order to obtain normativedevelopmental data.

When we reported the ontogenetic changes of local cerebral glucose metabolic rates for glucose(LCMRG1c) obtained with PET and2-deoxy-2['8F]fluoro-D-glucose(FDG), we had already measured

23Imaging Human Brain Development with PET •Chugani and Phelps

EDITORIALImagingHumanBrainDevelopmentwithPositronEmissionTomography

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•••

‘t@_

ofthe phylogenetically newer dorsalprefrontal regions. The metabolicmaturation of frontal cortex alsoprogresses from inferior to phyogenetically newer superior levels.Functional maturation of thesefrontal cortical regions coincideswith the appearance of higher cortical and cognitive abilities ( 10). By1 yr. LCMRG1c patterns qualitatively resemblethat of the normalyoung adult.

Quantitative analysis of LCMRGIcduring development (Fig. 1) revealed that the brain follows a proiracted glucose metabolic maturational course. Neonatal LCMRGIcvalues, which are about 30% lowerthan adult rates, rapidly increase toexceed adult values by 2—3yr in thecerebral cortex and remain at thesehigh levels until about 8—10yr,when LCMRG1c declines to reachadult rates by 16—18 yr (11).

The biologic significance of thevarious segments of the LCMRG1cmaturational curve remains to befully understood. We have postulated that the ascending portion ofrapid LCMRG1c increase corresponds to the period of rapid overproduction of synapses and nerveterminals known to occur in thedeveloping human brain during thattime period (2,3). The “plateau―period (Fig. 1) during whichLCMRGIc exceeds adult values cor

responds to the period of increasedcerebral energy demand as a resultof transient exuberant connectivity.This phenomenon appears to becommon to many species duringbrain development and is associatedwith a significant degree of plasticityin the brain. That segment of themetabolic maturational curve describing the LCMRG1c decline corresponds to the period of selectiveelimination or “pruning―of excessive connectivity, and marks thetime when recovery of function following brain insult markedly diminishesin the human (12). We believethat the in-depth analyses ofLCMRG1c maturational trends inhumans that can be accomplishednoninvasively with PET will ultimately yield an important index ofbrain plasticity. It is hoped thatthese data will provide criteria forprejudging the robustness of cornpensatory reorganization of thebrain to injury or necessary surgicalremoval of diseased regions.

The potential of expanding PETtechnology to assess a variety ofother biochernic and biologic processes important in the developingbrain is indeed exciting. In this issueofthe Journal, O'Tuama et al. (13)illustrate how age-related changes of[‘‘C]L-methioninetransport fromblood to normal frontal cortex canbe measured with PET. These in

vestigators demonstrate that bloodto-brain transport of [‘‘C]L-methionine in children exceeded that ofadults, suggesting a developmentalaccommodation of cerebral metabolic and synthesis requirements ofamino acids. Furthermore, competitive inhibition of [‘‘C]L-methionine uptake by neutral amino acidcarriers in the brain was already established by 4.6 yr. The strategy employed by O'Tuama et al., whichenabled such measurements to bemade in children, was to study onlypatients with brain tumors, sparingthe regions analyzed. The radiationexposure from PET in these patientsis not an issue because of the muchhigher radiation therapy doses administered to such patients.

O'Tuama et al. (13) purposelyrestricted the model analysis to thefirst 2 mm of tissue data to isolateunidirectional transport by neutralamino acid carriers. They offer presumptive and literature evidence tosupport the notion that these increases in neutral amino acid trans

port capacity during early childhoodare to meet the high protein synthesis requirements of the developingbrain. This could be definedexplicitly by performing studieswith L-[l-―C]leucinewith a formalcompartmental model that allowsmeasurement ofthe individual ratesof facilitated transport, protein syn

FIGURE 1Temporalcourseofchanges inLCMRGIc duringdevelopment.Top: Graph of cortical LCMRGIC in ,anole/min/100 g for thehuman. Dashed line is average adult value. Second row:Density of neuronal processes in human cortex at birth(sparse),at 6 yr of age (exuberant),and young adult. Thirdrow: PET images of LCMRGIc for a mid-level section at 5days of age (note low cortical and subcortical LCMRGIC,exceptfor phylOgenetiCallyolderthalamus),6 yr of age(exuberant),andyoungadult.Fourthrow:LCMRGICusing[‘4C]-2-deoxyglucoseautoradiographyin the cat to show the samedevelopmentalpattern as observed in the human. The agesin imagesfrom left to rightare birth, 60 days, and adult. In allimages, red is the highest value of LCMRGIc, with orange,yellow, green, and blue representingprogressivelylower values.

U 15Y_•d Al.

20 24

Human

Cat a24 The Journal of Nuclear Medicine •Vol. 32 •No. 1 •January1991

@.2o

L@I@Os

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thesis, and amino acid metabolism(14,15). Labeled methionine could

also be used by employing the compartmental model of Bustany andComar (16). Both approaches require knowledge of the model assumptions, extensive kinetic measurements, and biochemical analysisof plasma.

Where do we go from here? Sincethe neutral amino acid carrier system is only one of many components that contribute to the synthetic and functional processes ofthe developing brain, much workremains to be done. Data ofO'Tuama et al. (13) need to be expanded to include particularly children in the younger age group. It isour supposition that a developmental rise of protein synthesis tolevels in excess of adult values, corresponding to the formation of neuronal processes and synaptic connections, must precede the rise inLCMRG1c.This is based upon theassumption that the major portionofexcessive LCMRG1c described inour developmental studies is tomeet the functional requirements ofthe exuberant production of established synapses, since protein synthesis is not a process with highenergy requirements. This is supported by the fact that synaptic density in the human cortex rises to apeak by about 1—2yr of age (2,3),whereas LCMRG1c peaks a year ortwo later (Fig. 1). Stated differently,neuronal processes and synapticconnections must be constructed(protein synthesis) before they canfunction (energy consumption ofsynaptic maintenance and firing).This, however, remains to be experimentally proven.

Normative developmental datamust continue to be acquired inchildren with strategies that remainwithin ethical guidelines. These datamust not only include those biologicprocesses mentioned above but alsothe ontogeny of specific neurotransmitter systems and other processesas new assay methods with PET become available. Studies in humans

must be supplemented not only bysimilar studies in animals, but thiswork must be the origin of shapingquestions and experimental paradigms for much more rigorousmechanistic and ultrastructuralstudies in animal models, tissue seetions, cell cultures, and isolated molecular systems. Taken together, thiscomprehensive approach will enhance and deepen our fundamentalunderstanding of the rules governing normal human brain development.

As we gain a better understandingof the essential building blocks innormal brain development, we willbe better equipped to apply theserules and knowledge to understanding disorders of defective brain development (e.g., microcephaly,Down's syndrome, learning disabilities,etc.)and hopefully to favorablyaffect the clinical course of theseunfortunate individuals. The use ofPET to identify and map the areaofresection, as well as assess the integrity of the remaining brain, in thesurgical treatment of infants andchildren with refractory seizuresstands as an example of the clinicalbenefit that can be realized fromresearch studies of normal and abnormal development of the brain(17,18).

Harry T. ChuganiMichael E. Phelps

UCLA School of MedicineLos Angeles, California

REFERENCES

I. Rabinowicz T. The difFerentiated maturation of the human cerebral cortex.In:Falkner F, TannerJM, eds. Humangrowth. volume 3. Neurobiology andnutrition. New York: Plenum: I979:97—123.

2. Huttenlocher PR. Synaptic density inhuman frontal cortex—developmental changes and effects of aging.BrainRes l979;l63:l95—205.

3. Huttenlocher PR, de Courten C, GrayLI, vanderLoosH. Synaptogenesisinhuman visualcortex-evidencefor synapseeliminationduringnormaldevelopment. Neurosci Leti I982:33:247—252.

4. Changeux JP, Danchin A. Selectivestabilization ofdeveloping synapses asa mechanism for the specification ofneuronal networks. Nature I976:264:705—712.

5. Jacobson M. Developmental neurobiology, 2nd edition. New York:Plenum; 1978:302—307.

6. KennedyC, SokoloffL. An adaptationof the nitrous oxide method to thestudy of the cerebral circulation inchildren: normal values for cerebralblood flowand cerebral metabolic ratein childhood. J C/in Invest 1957:36:1130—1137.

7. Phelps ME, Hoffman EJ, Mullani NA.et al. Application of annihilation co..incidence detection to transaxial reconstruction tomography.J NuciMed1975:16:210—224.

8. Phelps ME, Mazziotta JC. Positronemission tomography: human brainfunction and biochemistry. Science1985:228:799—809.

9. Chugani HT, Phelps ME. Maturationchangesin cerebral function in infantsdetermined by [@F]FDG positronemission tomography. Science 1986:231:840—843.

10. Kagan J. Do infants think? ScientificAmerican 1972:226:74—82.

11. Chugani HT, Phelps ME, MazziottaJC. Positron emission tomogr@phystudy of human brain functional development. Ann Neurol 1987:22:487—497.

12. Chugani HT, Hovda DA, VillablancaJR. et al. Metabolicmaturationof thebrain: a study of local cerebralglucoseutilization in the developing cat. JCereb Blood Flow Metab 1990:inpress.

13. OTuama LA, Phillips PC, Smith QR,et al. L-Methionine uptake by humancerebral cortex: maturation from infancy to old age. J Nut! Med 1991:32:16—22.

14. Keen RE, Barrio JR. Huang SC, et al.In vivocerebral protein synthesisrateswith leucyl-transfer RNA used as aprecursor pool: determination of biochemical parameters to structuretracer kinetic models for positronemission tomography. J Cereb BloodFlow Metab 1989:9:429—445.

15. Hawkins RA, Huang SC, Barrio JR.Ct al. Estimation of local cerebral pro

tein synthesis rates L-[1) ‘C]leucineand PET: methods, model, and resultsin animals and man. J Cereb BloodFlow Metab I989;9:446—460.

16. Bustany R, Comar D. Protein synthesis evaluation in brain and other organs in human by PET. In: ReivichM, Alavi A, eds. Positron emissiontomography. New York: Alan R. Liss,Inc.:1985:183—201.

Imaging Human Brain Development with PET •Chugani and Phelps 25

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Selected manuscriptsfrom theissuesof TheJournalofNuclearMedicine published 15and 30

yearsago.Edited by F.F.Mand

17. Chugani HT, Shewmon DA, PeacockWi, ShieldsWD, MazziottaJC, PhelpsME. Surgical treatment intractableneonatal onset seizures:the role of pos

itron emissiontomography. Neurology1988;38:l178—I188.

18. Chugani HT, Shields WD, ShewmonDA, Olson DM, PhelpsME, Peacock

WJ. Infantile spasms. I. PET identifiesfocalcorticaldysgenesisin cryptogeniccases for surgicaltreatment. Ann Neurol 1990;27:406—4l3.

mark. After counts per minute are taken,tissue background is measured over theupperposteriorchest.Immediatelyaftervoiding, bladder measurement is repeatedto check for retention.

RESULTSThe present procedure with its supplemental bladder recording and in vivomeasurementoftracerexcretionhasbeenemployed during the past several monthsin the performance of323 renocystograms

using‘311-hippuran.Themorerapidrenalaccumulationandexcretionofhippuranisreflected in the renograms by more steeply

rising and falling tubular and excretionsegments. In marked constrast, the miokon renogram has rather shallow tubularand excretion segments and peak activityis reachedin7.5mmversus2.5 mmwithhippuran.

Hippuran, by virtue of its rapid renalturnover and organ specificity, is the idealtracer agent lix the radioistopic renogram.The greater sensitivity in detecting renaland upper urinary tract abnormalities has

been demonstrated by comparative studieswith other test agents in the same patientsand by serial renograms in individualswith fluctuating renal disease.

necrotic myocardium. In PAS-stained seetions, differences in intensity of stainingwere accounted for on the basis of abundantPAS-positiveglycogendeposits,glycogen depletion and diffuse diastaseresistantPAS-stainingofnecroticmusclecells in the infarcts, and PAS staining ofneutrophils in the infarcts.

The resultsofthis studyshowthatinfarct size can be adequately measured with

99mTcPYPmyocardial scintigrams indogs with proximal left anterior arterialligation. The potential application of thisapproach in man is uncertain, but the dataprovide sufficient encouragement forfuture clinical evaluation ofthis imagingtechnique. Additionally, comparativemeasurements of infarct size in experimentalanimalsand patients,usingprecordial mapping and creatine phosphokinaseclearance measurements, should be made.

Quantitative in vivo measurements oftracer excretion are made immediatelyafter completion of the 10-15-mmqualitative test.

Urinal:,; Excretion Measurement.Bladder phantom studies were made toselect an optimum arrangement of detection equipment for accurate in vivo bladder measurements. The detector utilizedhas a 2x2-inch thallium-activatedsodiumiodidecrystalhousedina shield.Thesurface of the crystal is retracted 4 inchesfrom the opening ofthe shield to which amulti-stagecollimatoris attached.

With the patient positioned against awalltosecureimmobilization,thecentering stick ofthe detector is placed againstthe upper border of the symphysis pubisand pressure is exerted along its axis toensure a firm location at this bony land

dial scintigrams to estimate acute MI indogs.

Mull dogs weighing between 15 and35kgwereanesthetizedwithi.v.choloralose and ventilated with a Harvard respiratorusing95%O2and5%CO2.Imaging was performed 1hr after an i@.injection of 3 mCi of 99―Tc-PYP.Scintigramswere made using a Searle RadiographicsPho/Gamma III HP camera with a highresolutioncollimator.Data were collectedby a PDP-8/I computer interfaced to thescintillation camera and recorded onseven-track magnetic tape. Histologicquantification of infarct size was performed by utilizing the methods of Alonso

and Reimer.In mosthistologicsections,areasof

infarction were relatively homogeneousand contained relatively small borderzones with mixtures ofnecrotic and non

26 The Journal of Nudear Medicine •Vol. 32 •No. 1 •January1991

JANUARY 1961

The RadioIsotope RenocystogramDolores E. Johnson, George V.Taplin,EarlK. Dora,andJaneHayashl

The radioisotopic renogram is a tracermethod for evaluating individual kidneyfunctionandpatencyoftheupperurinarypassagesbyexternalgammarayscintillation counting techniques. Certain modifications have improved the renogramsince its introduction in 1956,but it maybe improved further in several ways.

This work demonstrates an efficientarrangement of detection equipment andpoints out the superiority of ‘311-labeledhippuran for this procedure.

METHODODLOGYRenog,um. Thepatientis seatedcom

fortably in the “renogramchair―to ensureimmobilization. Kidney probes arecentered over the renal areas against theskin. A third detector, aimed at the bladder, iscenteredatthe sacrococcygealjunction. Tracerdose is measured in a syringebefore and after injection in an ‘@‘Icalibratedphantom. A testdoseofO.6 mCi‘311-hippuranperkilogramofbodyweightis used to obtain peak count rates of70,000-90,000 cpm in normal subjects.

JANUARY 1976Measurement of Acute MyocardlalInfarcts In Dogs with Technetium99m-Stannous PyrophosphateScintigrams

ErnestM.Stokely,L. MaximillianBuja,SamuelE. Lewis,RObertW.Parkey,Frederick J. Bont, Robert A. Harris, Jr.,andJamesT.Wlllerson

Cardiac pump failure in patients followmgacuteMI has been shownto be directlyrelatedtothe massofirreversiblydamagedmyocardialtissue. Estimatesofinfarct sizefollowingacute MI could, thereibre, haveimportant implications for patient treatment.Severalmethodshavebeenusedtomeasureinfarctsizeinanimals,butnonehas gained universal acceptance. Thepresent study assesses the use of @mTc@PYP (stannous pyrophosphate) myocar

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1991;32:23-26.J Nucl Med.   Harry T. Chugani and Michael E. Phelps  Imaging Human Brain Development with Positron Emission Tomography

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