Human Bain Mapping 28:474 481 (2007) REVIEW ARTICLE Stuctual Bain Magnetic Resonance Imaging of Pediatic Twins Jay N. Giedd, 1 * James Eic Schmitt, 2,3 and Michael C. Neale 2,3 1 Child Psychiaty Banch, National Institute of Mental Health, National Institutes of Health, Depatment of Health and Human Sevices, Bethesda, Mayland 20892 2 Viginia Institute fo Psychiatic and Behavioal Genetics, Viginia Commonwealth Univesity, Richmond, Viginia 23298 3 Depatments of Psychiaty and Human Genetics, Viginia Commonwealth Univesity, Richmond, Viginia 23298 Abstact: To exploe the elative impact of genetic and nongenetics factos on human bain anatomy duing childhood and adolescence development, a collaboative team fom the Child Psychiaty Banch of the National Institute of Mental Health and Viginia Commonwealth Univesity is applying stuctual equation modeling to bain mophometic data acquied via magnetic esonance imaging fom a lage sample of monozygotic and dizygotic pediatic subjects. In this epot, we discuss methodologic issues elated to pediatic neuoimaging twin studies and synthesize esults to date fom the poject. Cuent sample size fom the ongoing longitudinal study is appoximately 150 twin pais. Consistent themes ae: (1) heitability is high and shaed envionmental effects low fo most bain mophometic measues; (2) the ceebellum has a distinct heitability pofile; (3) genetic and envionmental factos contibute to the development of the cotex in a egional and age specific manne; and (4) shaed genetic effects account fo moe of the vaiance than stuctue specific effects. Undestanding of influences on tajectoies of bain development may shed light on the emegence of psychopathology duing childhood and adolescence and ultimately may guide theapeutic inteventions. Hum Bain Mapp 28:474 481, 2007. VC 2007 Wiley-Liss, Inc. Key wods: child development; adolescent development; heedity; neuoanatomy; ceebellum INTRODUCTION The Child Psychiaty Banch of the National Institute of Mental Health is conducting a longitudinal pediatic bain *Coespondence to: Jay N. Giedd, Bain Imaging Unit, Child Psychiaty Banch, NIMH, Building 10, Room 4C110, 10 Cente Dive, MSC 1367, Bethesda, MD 20892, USA. E-mail: jg@nih.gov Received fo publication 12 Decembe 2006; Revision 27 Febuay 2007; Accepted 5 Mach 2007 DOI: 10.1002/hbm.20403 Published online 16 Apil 2007 in Wiley InteScience (www. intescience.wiley.com). imaging study of typically and atypically developing childen and adolescents. The long-tem stategy is to: (1) map the tajectoies of bain mophometic measues; (2) discen the influences on those tajectoies; and (3) apply undestanding of influences to guide inteventions. The fist component, mapping developmental tajectoies, is well undeway and indicates a geneal patten of inceasing white matte volumes and inveted U shaped tajectoies of gay matte volumes with diffeent peak volumes fo diffeent egions [Giedd et al., 1999]. One of the fundamental challenges fo component two, undestanding what factos affect the tajectoies, is to discen genetic fom nongenetic influences. Twin studies ae best suited to addess these types of questions and theefoe, in 2001, we VC 2007 Wiley-Liss, Inc.
Pediatic Neuoimaging of Twins began collaboating with a team of expets in twin eseach at the Viginia Institute fo Psychiatic and Behavioal Genetics and Depatment of Psychiaty, Viginia Commonwealth Univesity. Pediatic neuoimaging twin studies, although pesenting moe methodological obstacles, may offe advantages ove adult studies in some domains. Most neuopsychiatic disodes manifest duing childhood o adolescence and even many disodes with adult onset, such as schizophenia, ae inceasingly conceptualized as developmental in oigin. Studying the developing bain in pemobid conditions o ealy in the couse of illness, befoe the effects of long tem impaiment o teatment inteventions, may shapen the intepetation of bain diffeences to the coe featues of the illnesses. Paticulaly impotant is to conside that diffeences in the tajectoies of development may in some cases be moe infomative than the final adult diffeences. Fo instance, in ou longitudinal study, looking at the elationship between cotical thickness and IQ diffeences in age by cotical thickness developmental cuves wee moe pedictive of IQ than diffeences in cotical thickness at age 20 yeas [Shaw et al., 2006]. In this epot, we will discuss some of the methodologic consideations and challenges in conducting pediatic neuoimaging twin studies and summaize cuent esults fom the Child Psychiaty Banch/VCU collaboative poject. METHODS Study Design Initial powe analysis pojected sample size equiements of 100 MZ pais and 100 same sex DZ pais (50 of each sex) scanned at 2-yea intevals fo at least thee useable longitudinal data points. Subjects All subjects wee sceened via an initial telephone inteview, paent and teache ating vesions of the Child Behavio checklist [Achenbach and Ruffle, 2000], and physical and neuological assessment. Exclusion citeia included psychiatic diagnosis in the subject o a fist degee elative, and head injuy o othe conditions that might have affected goss bain development. Fo twin ecuitment, advetisements specified that the MRI study sought twins between the ages of 5 and 18, with no leaning disabilities, neuological poblems o behavioal disodes. The sceening pocess involved phone inteviews, behavioal questionnaies mailed to paents and teaches, an in-peson clinical inteview, family histoy assessment, as well as a physical and neuological exam. Exclusion citeia included having a lifetime histoy of physical, neuological, o psychiatic abnomalities, leaning disabilities, o psychiatic illness oneself, o in eithe one fist-degee elative o moe than 20% of seconddegee elatives. Appoximately one in fou families esponding to the advetisements met inclusion citeia. Twins wee included in the analysis only if quantifiable MRI scans fee fom motion o othe atifact wee obtained on both twins at the same age. Witten assent fom the child and witten consent fom a paent wee obtained fo each paticipant. The study potocol was appoved by the institutional eview boad of the National Institute of Mental Health. Zygosity was detemined by DNA analysis of buccal cheek swabs using 9-21 unlinked shot tandem epeat loci fo a minimum cetainty of 99%, by BRT Laboatoies (Baltimoe, MD). Image Acquisition All subjects wee scanned on the same GE 1.5 Tesla Signa scanne using the same thee-dimensional spoiled gadient ecalled echo in the steady state (3D SPGR) imaging potocol (axial slice thickness ¼ 1.5 mm, time to echo ¼ 5 ms, epetition time ¼ 24 ms, flip angle ¼ 458, acquisition matix ¼ 192 256, numbe of excitations ¼ 1, and field of view ¼ 24 cm). A clinical neuoadiologist evaluated all scans and no goss abnomalities wee epoted. Image Analysis Image analysis was pefomed via collaboation with the Monteal Neuological Institute. The native MRI scans ae egisteed into standadized steeotaxic space using a 9 degees of feedom linea tansfomation [Collins et al., 1994] and coected fo nonunifomity atifacts [Sled et al., 1998]. The egisteed and coected volumes ae segmented into white matte, gay matte, and ceebospinal fluid (CSF) using a neual net classifie [Zijdenbos et al., 2002]. Region of inteest analysis is pefomed by combining tissue classification infomation with a pobabilistic atlas deived fom an independent sample of adult scans. The egions that have been validated by compaison with othe methods ae the following: midsagittal aea of the copus callosum, volumes of the ceebellum, caudate nucleus, and lateal venticles, and gay and white matte volumes of the total ceebum, fontal lobes, paietal lobes, and tempoal lobes [Collins et al., 1995]. Methodologic tools Statistical Analysis A geneal objective of twin studies is to divide the vaiance in a phenotype into genetic and nongenetic souces by analyzing diffeing coelations among MZ and DZ twins [Neale, 1992]. Stuctual equation modeling (SEM) and its mathematically equivalent visual analog, path analysis, povide a poweful and flexible famewok way to model causal and coelational influences on both obseved and unobseved (i.e. latent) taits. SEM analyses typically use numeic optimization of a likelihood function to poduce paamete values that povide the best fit to 475
Giedd et al. the data [Neale et al., 2002]. The optimization stategy begins with moe o less abitay stat values fo model paametes and calculation of an initial fit based on those stat values. The output infoms modification of the paametes and the pocess is epeated until the likelihood of the obseved data is maximized, that is, the model best appoximates the data. Fo continuous measues such as volumetic data, the calculation of likelihood is based on the pobability distibution function. If thee ae m obseved vaiables on each twin, the multivaiate nomal pobability density function of a column vecto of twins obseved scoes x i is given by: L ¼j2pj 2m=2 exp 1 2 ðx i u i Þ 0 1 ðx i u i Þ ð1þ Figue 1. Path diagam depicting the classical ACE model fo univaiate vaiance component analysis. With MZ and DZ twins, thee latent vaiables can be identified epesenting an additive genetic facto (A), a shaed envionmental facto (C) and a unique envionmental facto (E). Paths depict the stength of the elationship between latent factos and the obseved phenotype and ae analogous to beta weights in linea egession. a epesents the genetic coelation between twins (1 fo MZ pais, Â1/2 fo DZ pais). whee S is the pedicted covaiance matix, and u i is the (column) vecto of pedicted means of the vaiables [Neale, 2003]. This epesents the likelihood of obseving ecod i, given the population mean and vaiance and assuming nomality. The joint likelihood of the N independent pais in the sample is computed as the poduct of the likelihoods of all pais. Mx, a softwae pogam developed by one of the authos (M.N.) is used to pacellate the vaiance of neuoanatomic stuctues into genetic and nongenetic factos; depending on the hypothesis being tested, othe details will vay fom model to model. Mx is the most commonly used softwae package fo the analysis of genetically infomative samples, and can also be applied to many types of multivaiate poblems that ae likely to manifest duing the couse of the poject. Path diagams can be constucted to model the vaiance attibuted by diffeent latent vaiables (see Fig. 1). In models fo classical twin studies, thee latent vaiables ae usually defined: a, c, and e, epesenting additive Figue 2. The extended twin design. 476
Pediatic Neuoimaging of Twins Examples of extensions into multivaiate analyses. Fo simplicity, only one membe of a twin pai is shown in each model. A: Univaiate analyses un in paallel with fou obseved vaiables. Thee is no covaiance between phenotypes. B: Cholesky decomposition, with only genetic factos shown. The tiple Cholesky would Figue 3. include a seies of C and E factos with the same patten as A. C: Independent pathways model. D: Common pathways model. The influences of A, C, and E ae mediated though common, latent phenotypes (LP). genetic, shaed envionmental, and unique envionmental dimensions, espectively [Evans et al., 2002; Neale, 1992]. The E tem also includes measuement eo. Paametes A o C o both can be emoved fom the model to geneate submodels (i.e. AE, CE, and E) that can be tested via likelihood atio (g 2 ) test. The models can also include paametes to account fo effects of age and sex on mophometic measues. Futhe, these models can be expanded to include siblings of twin pais and singleton families, which can geatly incease powe to detect influences of the shaed envionment (see Fig. 2). This extended twin design assumes that the shaed envionment opeates similaly in both twins and singleton biths, with espect to the phenotype of inteest. In ou sample, families contained a twin pai and up to thee additional siblings, o singleton families with up to five membes in total. The use of a lage singleton sample can incease pecision in the estimates of neuoanatomic vaiance due to a geate numbe of obseved covaiance statistics [Posthuma and Boomsma, 2000; Posthuma et al., 2000], as well as withinsubject covaiance in multivaiate models. Multivaiate analysis Multivaiate analyses allow assessment of the degee to which the same genetic o envionmental factos contibute to multiple neuoanatomic stuctues. Like the univaiate vaiables, these intestuctue coelations can be paceled into elationships of eithe genetic o envionmental oigin. This knowledge is vitally impotant fo intepetation of most of the twin data including undestanding the impact of genes which may affect distibuted neual netwoks and inteventions that may have global bain impacts. Multivaiate models can be simple extensions of the ACE model, but may also use infomation about cosstwin, coss-tait coelations that allows fo the detemination of which undelying factos cause phenotypes to 477
Giedd et al. covay (see Fig. 3). Multivaiate modeling also inceases the pecision of paamete estimates including the univaiate a, c, and e estimates since fa moe obseved statistics ae used. These popeties ae useful fo assessing the undelying causes of covaiance o fo modeling changes in phenotypes ove time with longitudinal designs. Thee ae thee commonly used multivaiate facto models in behavioal genetics analysis, the Cholesky decomposition, the independent pathways (i.e. biometic) model, and the common pathways (i.e. psychometic) model; path diagams fo each ae given in Figue 3. The most fully paameteized is the Cholesky decomposition, which deconstucts any n n positive definite vaiance covaiance matix into an n x n tiangula matix, postmultiplied by its tanspose, and places few a pioi constaints on the fitting of the data [Evans et al., 2002; Neale, 1992; SAS Institutes, 2000]. Cholesky models ae typically used as a satuated model against which the fit of moe estictive models may be compaed, o to calculate genetic coelations. Independent pathways models (IPM) allow genetic, shaed envionmental, and unique envionmental common factos to affect obseved vaiables diectly, while in common pathways models (CPM) these factos exet thei influence though a shaed, latent phenotype (Fig. 3C,D). In both models, each obseved vaiable is pemitted a esidual vaiance tem, which can also be pased into A, C, and E components. While IPMs ae conceptually simple, CPMs, equie fewe paametes (when the numbe of factos is constant acoss models, e.g., 1A, 1C, and 1E facto vs. Phenotypic facto) and thus ae favoed by the ules of pasimony. Both CPMs and IPMs ae nested submodels of the Cholesky decomposition, and fo a given numbe of common factos the CPM is nested within IPM. Depending on the numbe of obseved vaiables, both of these classes of models can be expanded to allow fo multiple genetic, shaed envionmental, o unique envionmental common factos. Age-by-heitability inteactions An impotant aspect of developmental twin studies is assessment of age by heitability inteactions (Age*A). Although longitudinal data is obviously bette suited to addess Age*A questions, a novel extension of the ACE model allows fo modeling age effects on phenotypic vaiance using coss-sectional data [Pucell, 2002]. The pinciple is simila to egession, but athe than affecting the mean phenotypic value, the modeato vaiable adjusts the magnitude of the influence of the latent vaiables A, C, and E on phenotype (see Fig. 3). Thus, in the inteaction model, the influence of the latent vaiable A on phenotype fo individual i and modeato vaiable M (in this case, age), is (a 1 + a 2 )*M i athe than simply a 1 Since the effects of these latent vaiables ae infeed though phenotypic vaiance and coss-twin covaiance, the esult of the expanded g e model is to allow fo changes in vaiance (i.e. heteoscedasticity) and covaiance of phenotype along the dimension of the modeating envionmental tait. The twin design allows fo the detemination of which vaiance component(s) ae esponsible fo the inteaction, and thus to test whethe these effects ae statistically significant. SUMMARY OF RESULTS TO DATE A univaiate study addessing heitability of bain mophometic measues [Wallace et al., 2006] and a multivaiate study addessing shaed genetic o envionmental effects acoss egions [Schmitt et al., 2007] have been the initial epots fom this ongoing poject. Univaiate Study The sample size fo this epot was 90 monozygotic twin pais, 38 same-sex dyzygotic twin pais, and 158 unelated typically developing singletons. Bain mophomety measues wee midsagittal aea of the copus callosum, volumes of the ceebellum, caudate nucleus, and lateal venticles, and gay and white matte volumes of the total ceebum, fontal lobes, paietal lobes, and tempoal lobes. Shaed envionmental effects (c2) wee negligible and additive genetic effects (a2) highly significant fo all stuctues examined. Additive genetic effects fo total ceebum and loba volumes (including gay and white matte subcompatments) anged fom 0.77 to 0.88, fo the caudate nucleus was 0.80, fo copus callosum 0.85, fo ceebellum 0.49, and fo the lateal venticles 0.31. Significant age-byheitability inteactions wee obseved with gay matte volume heitabilities deceasing ove time and white matte volume heitabilities inceasing ove time. Multivaiate Analysis A multivaiate analysis was pefomed on 127 pais of monozygotic twins (mean age ¼ 11.6, SD ¼ 3.3; age ange ¼ 5.6 18.7; 74 [58%] male, 53 female) and 36 pais of same-sex dizygotic twins (mean age ¼ 11.0, SD ¼ 3.7; age ange ¼ 5.5-18.2; 18 [60%] male, 12 female) [Schmitt et al., 2007]. The bain measues examined wee the ceebum, thalamus, lateal venticles, telencephalic subcotical nuclei, copus callosum, and ceebellum. In geneal, within-stuctue, coss-twin coelations wee substantially highe in the MZ than in the DZ twins, suggesting a stong genetic impact on bain volumes vaiation. Facto analysis indicated that much of the genetic effect was accounted fo by two common factos. One stongly influenced vaiance of ceebum, thalamus, and basal ganglia, with facto loadings (analogous to standadized patial egession coefficients) of about 0.85. This facto also accounted fo a substantial popotion of the genetic vaiance of the ceebellum, and had a low but statistically significant effect on copus callosum, but no 478
Pediatic Neuoimaging of Twins impact on lateal venticula volumes. The second genetic facto pedominantly compised the modest genetic effects on venticula volume, with a statistically significant negative facto loading on the basal ganglia compatment. Although the oveall contibution fom envionmental souces was much less than fom genetic, analysis indicated that two factos also accounted fo a substantial potion of the envionmental effects. One envionmental facto pimaily contibuted to vaiance in all deep stuctues (thalamus, basal ganglia, lateal venticles, and copus callosum), with the venticles negatively coelated with the othe vaiables. The second envionmental facto epesented shaed effects on the ceebum, lateal venticles, and ceebellum. Stuctue-specific factos contibuted fa less vaiance than the common factos with the exception of the copus callosum whee genetic factos specific to that stuctue accounted fo 69% of the vaiance. Less than 10% of the vaiance in copus callosum size could be explained by genetic souces that also affected othe stuctues in the analysis. DISCUSSION/SYNTHESIS Consistent themes fom analysis of data fom the ealy stages of this ongoing poject ae: (1) heitability is high and shaed envionmental effects low fo most bain mophometic measues; (2) the ceebellum has a distinct heitability pofile; (3) genetic and envionmental factos contibute to the development of the cotex in a egional and age specific manne; and (4) shaed genetic effects account fo moe of the vaiance than stuctue specific effects. High Heitability of Bain Mophomety Highly heitable bain mophometic measues povide biological makes fo inheited taits, and may seve as tagets fo genetic linkage and association studies. These intemediate phenotypes may incease the powe to detect quantitative tait loci (QTLs) influencing citical behavioal functions and liability to psychopathology [Gottesman and Gould, 2003]. A geate undestanding of the foces that guide bain development will help povide a heuistic fo developing and implementing moe effective inteventions in the teatment of bain-based disodes. Smalle stuctues, pehaps because of a geate popotion of measuement eo, tend to have lowe heitability values and white matte volumes tend to moe heitable than gay matte volumes. Lowe heitability fo gay matte is consistent with the notion of plastic synapses changing in esponse to envionment and activity. Ceebellum The ceebellum is the least heitable of the stuctues we have examined (although wide confidence intevals meit cautious intepetation). Pediatic ceebella development is also notewothy as being the most sexually dimophic and amongst the latest to each peak volume [Lenoot et al., 2005]. These featues make the ceebellum a pime taget fo pediatic neuoimaging studies. Pominent envionmental influences on ceebella development ae consistent with its pefeential susceptibility to insults such as alcohol, lead, o anoxia. Postnatal neuogenesis of ceebella Pukinje cells may also be elated to envionmental susceptibility [Welsh et al., 2002], although the elationship between this pocess and volumetic changes emains to be elucidated. Also unclea is whethe the unique development and heitability chaacteistics of the ceebellum ae elated to its divegence fom the othe egions soon afte neual tube fomation; while ceebum, copus callosum, and subcotical stuctues all ae deived fom the embyonic posencephalon, ceebella tissue is pimaily deived fom the ombencephalon [Kandel et al., 2000]. Age-by-Heitability Inteactions Vulneabilities of highly heitable neuopsychiatic illnesses such anxiety, bipola disode, depession, eating disode, psychosis, and substance abuse ae pesumably pesent at bith. Howeve, the peak age fo emegence of symptoms in all of these disodes is duing adolescence. Age elated changes in heitability may be linked to the timing of gene expession and elated to the age of onset of disodes. Knowledge of when cetain bain stuctues ae paticulaly sensitive to genetic o envionmental influences duing development could also have impotant educational and/o theapeutic implications. Fo loba volumes total vaiance attibutable to both additive genetic and unique envionmental factos inceased with time, though the popotion of that inceased vaiance attibutable to genetic o nongenetic factos diffeed between gay and white matte components. Specifically, fo white matte additive genetic effects account fo a geate popotion of the vaiance with inceasing age wheeas fo gay matte unique envionment effects account fo a geate popotion of the vaiance with inceasing age. As heitability is deived fom the popotion of vaiance accounted fo by genetic factos gay matte heitability thus deceases with age while white matte heitability inceases with age. Shaed Genetic Effects The multivaiate analysis demonstates that not only do genes play the pedominant ole in geneating the obseved volumetic divesity, but that most of the genetic vaiance is detemined by genes that ae shaed between the majo goss neual subdivisions. This finding is concodant with evolutionay genetic models of bain development which hypothesize global, genetically-mediated diffeences in cell division as the diving foce behind intespecies diffeences in total bain volume [Finlay and 479
Giedd et al. Dalington, 1995] as well as with the adial unit hypothesis of neocotical expansion poposed by Rakic [1995]. Compaative neuoanatomic analyses of multiple mammalian species have shown that total bain volume is highly coelated with egional volumes, iespective of egion (including neocotex, stiatum, thalamus, and ceebellum), and accounts fo the vast majoity (>96%) of the obseved volumetic vaiance in all egions measued except fo the olfactoy bulb [Dalington et al., 1999; Fishell, 1997]. Such stong coelations ae thought to eflect a genealized adaptation to specific selective pessues; although it is moe expensive, in tems of enegy, to expand the computational esouces of the entie bain when only specific functions ae needed, the molecula adjustments equied ae fa fewe than those equied to completely epatten goss neual achitectue. Theoetically, genetic associations between neuoanatomic stuctues could aise via numeous putative mechanisms; seveal geneal models can be consideed while intepeting the pesent data. Fist, bain volumes may be elated genetically via ubiquitous gene poducts involved in basic cellula metabolism, cell gowth, diffeentiation, o othe global pocesses expessed thoughout neuoectodemal deivatives [Rakic, 1995]. Fo example, functional vaiation in housekeeping genes o cell cycle egulatos might be expected to poduce genetic coelations between all bain egions that expess them (and pehaps othe tissues), if they poduce downsteam effects on volumetic measues via changes in cell polifeation o suvival. Second, coelations in bain volumes may epesent vestigial elationships geneated penatally between stuctues with shaed ontological oigins. Region-specific expession of tansciption factos duing neuoembyonic pattening would be one example of gene poducts poducing egional coelations duing embyogenesis. In this case, one would expect stonge genetic elationships among stuctues whose development diveged moe ecently (e.g., thalamic and hypothalamic volumes to be coelated via thei shaed diencephalic oigin). Thid, functional inteelationships between stuctues may geneate volumetic coelations via mophological changes associated with inceased connectivity. This hypothesis is essentially a genealization of the Potocotex model, which states that neocotical development is detemined by extinsic influences, such as effects of thalamic innevation [O Leay, 1989; Schlagga and O Leay, 1991]. Thus, one might expect stuctues in the visual pocessing netwok, such as V1 and the lateal geniculate nucleus, to be stuctually coelated despite being potentially unelated spatially o ontologically. Finally, genetic coelations may esult fom shaed supa-egional gene expession tiggeed postnatally, in the pesent data fom bith to the age of scan acquisition, appoximately mid-childhood. Though the unique envionment had a elatively mino effect on the volumes of the stuctues measued, ou elatively lage sample allowed us to descibe its ole on the coelations between stuctues with high pecision. We found that stuctues in spatial poximity wee significantly positively coelated via individual-specific envionmental factos shaed between multiple anatomic egions. In othe wods, the envionment tends to influence neaby stuctues similaly. CONCLUSION In the past decade few disciplines in neuoscience have undegone as damatic gowth as genetics and neuoimaging. Bain imaging studies of twins lie at the inteface of these bugeoning disciplines. Although still in its nascent stages and undepoweed to detect impotant nuances of gene bain elationships, these peliminay findings suggest a few emeging pinciples that may help guide ongoing investigations. 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