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Human Brain Mapping

2r I

1994)

OVERVIEW

Computational Approaches to Network Analysis in Functional Brain lmaging


Functional brain mapping iechniques have the poiential of revealing not only the activity of brain regions, but also the rclationships or interactions between reSrons. UnderstandinS neural interactions

iequires the development of computational approaches capable of analyzing brain aciiviiy in terms of funciional networks. Hufldr Brain Mapping has devoied this special issue io highlighi the significant
advances in developing computational approaches to neiwork analysis in neuroimaging. The eight articles in this issue are based on prsentations made at the

international symposium on "Computational Approaches to Neiwork Analysis in Fun.tional Brain lmaging," hld in Austin, Texas on April 25, 1994. It rprcsnts the firsi collection of papers in this area; and its purpose is to bring together ihe pioneerinS work done with ihese types of computational meth-

Th unifying theme of the various approaches presented is the focus on analyzing neiwork interactions to reveal the iichness ofbrain imaging data. The
articles also illustrate, with data from animals and humans, how these methods help to elucidate the complex funciional interaciions underlying normal

and abnormal brain activities. Computational approaches aie illmtrated with various applications io
normal sensorimotor and behavioral functjons using arditory, visual, and motor paradigms. In addiiion, ihe application of these approaches to investiSaie brain dystunciion is illustrated in diseases such as larl inson .. AlTheimer's. HuntinBton-. depre\cron, schizophrcnia, and othels. The first ihree articles deal with structural equation modeling, a method designed to quantify functional network interactions mediaied by specific neuroanatomical connections between brain regions. The a icle by Mclntosh and Gonzalez-Lima presents the theoreiicalbasis for boih covariance analysis of neural systems and neural strucrural equation modeling. ln the follorvo l994 Wily-liss, Inc.

ing articles, specific applications focus on auditory learning in rodents (Gonzalez-Lima and Mclniosh) and chan8es in motor system functional interactions in Parkinson's Disease before and after surgical inter vention (Grafton, et al.). The next three articles descdbe several other multivariate statisiical methods for mpd-urrng funclional inlFrd,lion- rn neuroimdginS data. The concepts of funciional and effective connectivity aie defined and expressed in relation to brain imaSingdaia setsin an articleby Fiiston. Th pdncipal components-based scaled subProfile model is Presented by Alexander and Moeller providint an inte$ation between biain imagnt and neuropsychiatric measures. clark et al. also use a pincipal comPonents approach to examine patient variability in HuntinSton's Disease. Poline and Mazoyei piesent a method to enhance the sensitivity ofactivation analysis throuth quantification of conti$ous clusters of activated voxels. In the 6nal article, Horwitz compares activation and covariance analyses and suggests ways in which neural modelint and neuroimaging maybe combined to yield a beiier undersianding of brain tunctionAlthough functional brain imaging techniques such as positron emissiorl tomography and autoradioSnphy have become central to brain research. relatively few studis take full advantage of neuroimadng data to quantify functional inieractions among brain regions. Therefore, there has been a need to review siate-olthe art applications of computational approaches to network analysis to provid a basis for future resrch in ihis area. It is hoped that this special issue will fulfill ihis need, and will help to advance the field of brain mapping into the realm of invesiigating the complex network interactions underlyinS brain

F. Gonzalez-Lima, PH.D

A.R. Mclntosh, rH.D. Peter T. Fox, M.D.

Human Brain llaDpinS2t2-2211994)

Structural Equation Modeling and lts Application to Network Analysis in Functional Brain Imaging
A,R. Mclntosh and F. Gonzalez-Lima
I obonrctu ot Nru,u\ in, Nnt;onnt Ltaittt : on AR,t t. Nntu'trlt tn Bethc.da. M0tutn d tA R M, ^. l.t. nnd D, pn, t neat al p.ythotor| an4 ! stitLte

nu^

lo, Hcntth

to, Ncu,u"

Unioersity

oJ Texas,

Austin,Tdns, (F.G.-L.)

in,r.

elements. The te.hnicaifoundations for neural strucrural equaiion modets are p.esenled, emphasizing the ability to make inlercntial compansons ro evatuaie the experimentat changes in path coefficienrs. Simulaled data sets were used io tesr the effecrs of omitted regions and orn ted-conn".iio".. rn",".o." suggested that shuctural modelinS algorithns can give hints as to possible exrernat influences and missingpaths, but that the finaldecision as ro modelmodifications requires rhe quidance of the .esealcher. The utilit), ofanatomically based oodels to disringuish between the direct etfecl of one region on anorner, and indirect effecis mediated through inte ening regions, is demonsrrated in an empin;al daia set that examined the effects of darkness o! partemed light on rhe metabotic activiry In the rai v,suat sysrem. lhe anatomical ffamework lor the structural equaiion models rcvealed that rhe rotat impaci of ascending thalamoco.tical influences was modified by corticocortical inreraciions. Extensions ofsiructural eouation modeling to human biain imaging erperimenrs are presenred. We con.lude by suggesting rhar neural covanances may be a more accurare way to examine the dynamic functional ofsanizarion ;f ihe central

Abstracl: The analysis ofbrain imagingdata has recently focused on rhe examination of the covanances or etivity among neural regions during differenr behaviors. We present some of rhe rheorerical and iechnical issues surounding one of rhese covarian.e-based meth;ds: structural equaiion modeling. tn srruclural equation modelin& conneciions between brain areas are based on known nedroanarom, and the.inieftegional oaiances of activity are used to calculare path coefficienrs represenring the magdruoe of the,influence of a.h direltional parh. The togic behind the use of structural eqrarion;odeling stems rrom ihe sug8e\hon thar bdrn functjon rs rhe resutr ofchanges in the covariances ofactivity amongneural

nervoussystem. !t9e4wilq.u$,rnc,

Ky words: path analysis, neural parhwav, neural systems, visual sysiem, rat, human, 2_deoxyglucose, regional cerebral blood flow, positron ehission romography

INTRODUCTION

Functional neuroimaSing techniques nave provided a unique opportunity to examine simultaReceivd forpubli.ationJune 23,1994; revision accepted A!8ust 24, Addrss reprinr requests to A.R. Mclntosh, ar his presenl addiess: Rotman Research Institute, Baycrsr Centre for ceriabic Carc, 3560 BathursrSkeet Toronto, Onrano, M6A 2E1 Canada

neously the aciivity wiihin the eniire brain of a singl subject. New data analysis methods have also taken ad\dnlaBe oJ ll-is opporlunrt). Imrge averaging a.rosr

subiecls. 5ubird,lion methods, stdlicli.dl pardmetric


maps [Fox et al., 1988; Friston et al., 1991j, and particle or cluster analysis lPoline and Mazoyer,1993, Roland et a1.,19931 represent a few of rhe innovarive methods for increasing the sensitivity of data analyses to locate

chan$s in regonal metabolic activity. The use of


more Eensitive analytic techniques is particulaily im-

1994

Wiley-tiss, Inc.

Stmctural Modelins ofBrai. Inreractions

portant for mappint studies of behavioral funciions when meiabolic changes are subtle. Recent trends in the analysis of brain imaging data have focused on ihe intera.tions amontbrain regions lFriston et a1.,1993a,b; Horwitz et a1.,1992a,b, Colden bert et al., 1989; La8rdze, et al., 1993; Mclniosh and Gonzalez-Lima, 1991r Moeller and Strother, 19911. They all extract informaiion about neural interactions lhrouSh decomporrhon of inrerregronrl .ovdndac(of activiiy. One of these methods is structural equaiion modeling or path analysis. It has proved to be a powerful way to combine functional neuroimaginB data with anatomical circuitry io determine the func tional neuroanatomy underlying a particular iask. We have applied structural equation modeling to autoradiographic 2-deoxyglucose (2-DG) and fluorodeoxytlucose (FDG) data obiained from rats in difierent behavioral paradigms lMclntosh and Conza]ez-Lima, 1991, r992a, 1993, 19941. More recently, siruciural equatiorl modeling has been applied to human brain imaginS data obtained from posiiron emission tomographic (PET) measures of regional cerebral blood flow (rCBF) lMclntosh et al., 1994a,b1. The toal of ihis paper is to explain the application of structural equation model ing to tunctional brain imaging data. The theoretical and technical issues of siructural equation modeling in its Seneral use have been extensively researched
le.g-, Bentler,1985;

expedments. A contrast of daia-driven versus iheory-driven approaches to modeling is then discussed. We conclude this paper by suggestinS that , o\ urid'rce baced melhods, b hich e\plain brain opprdtions in the context of funciional interactions, will provide a more realistic picture of the relationship of brain activity and behavior.

in8

WHY STUDY COVARIANCES?


The iraditional form ofdata analysis in all neurosci erce iechnique. h"s been to lool for differen,e. in Foup or condition means on the measured variable,

whether behavioral (e.9., perlormance on a neuropsychology test) or physiolodcal (e.9., action potentials per second/ isotop incorporation). Brain imaging is ro e\ceplion lo lhi-. dnd focu5inS on (han8e\ in medn regional activity has been a successful approach. For co\ d,idnce-bJ-ed rnd\.e. ro be useful rn neurormaSin& thy must make a significant conidbution to the understanding of the daia seis beyond what could be

deived from analysis of mean regional activity. Covariance relationships can span many temPoral and sPatial domains, from milliseconds to minutes and from

.in8le npuronr lo neu'al en.emble. and brdin ireJ-. T\lrdordinrr) in,i8hr. hdve bpen garned by e\dmining covaiancesat fine spaiialand temporal resolution,

Berrt

1985; Bollen, 1989, Boomsma,

198s, Fredman, 1987; HayduK 1987, Jdreskot, 1973; Jdreskog and Sdrbom, 1979, 1989; Loehlin, 19871, so ihe focus here is on isslles felated to the application of structural equation modeling to neural data

Since interegional covariances

of activiiy are the

basis of all network analytic techniques, we will begin

by suggesting that the fundamental organization of rhe cFnlral nervou..)slem mdle. ir ideal ior .ovdriance analysis. From that we will present the basic iheory underlying structural equation modeling as
applied to the central nervous system. Our application

in the case of sintle neuron electrophysioloSy [AeItsen et al., 1987i Opticon and Richmond, 19871 and across shori temporal intervals but larter spatial extents using evoked potentials lcevins et al., 1985; Gevins and Cuiillo, 19931. Wiih brain imaging and siructural equaiion modeling, the issue is whether 5imilar r'1riShrs . an be gJrned frol.l e\anininS covari ances based on iime-iniegrated activity measurs of
ensembles or brain regions. Expressed in ierms of neural sysiems, a measure of

of structural equation modeling to neural

systems

maks us of the neuroanaiomy to define a network and io express the interactions among brain re$ons.

Since the method is a modeling iechnique, it often requires simplifyint assumptions about the anatomy ihai includes leaving out minor connections and, on occasion, brain areas. The effects of an incomplete anatomical model, and the omission of re$ons that

have an impact on other regions included in the modelwillbe examined usint simulated daia sets. The utility of anatomically based models in the theoretical inteipreiation of a neural struciural equation model will then be presented, followed by recent extensions of -lruclur"l equdlron modFlinB In hu rdn brdrn inaS

covaiarce represents the de$ee io which the activi ties of iwo regions are related to one another, or how they vary togeiher. Ahigh covaiance between areas A and B means that if area A increases its activity, so too will B (in the case of a positive covadance). Covariances are studied in many scientific disciplines, but in neural systems, covariances of ativity have a special meaning. The dependent variables (regional activity of brain areas) are anatomically connected to one another, while in oiher disciplines, such as social science, there may be no a priori connective relahonships between dependent variables. More formally, the central nervous sysiem is unique

in that ii is composed of

numerous interconnected elements ran8inS from single neurons to entire ensembles. These connections range from local intra-

Mclblosh and Gonzalez-Lima.

newous sysiem site must come about throuSh a change in the influences of one or more affereni pathways. For peipheral sensory receptors/ activity changes are the result of environmental stimulation except where central sites influence the receptors (olivocochlear bundle). Under physiological condiiions, possible exceptions might be found in the diftuse cent'al ede\1. ot no.1 neurondl ofi8in reg.
peripheral hormonal or hemodynamic changes). Since one neuml element can influence the activity of arld therefore th vadance of another, the relationship btween neural elemenis can be quantified asa covariance. Therefore, interaciions between neural elements can be detecied by examinnlg ih covariances of measured activity within the central nervous system. The Seneral organizational prnrciples of the ner
vous system ouUined above suggest that l7mi, /lr rctrox is the rcsult af chatlges in the catrrianccs anang neural clc,rerls. The traditional emphasis on the analysis of changes in regional activity alone is more in line with

regional connections among neurons, io inierregional connections amongensembles of nurons across brain areas. ThouSh perhaps somewhat obvious, it is worth nohng thai communication beiween neural elements lneurons or ensembles) is along these interconnec, tions and these communications underlie brain funciion. It iollo$'s from this that a change in the observed activity of any element results from a change in ihe communication with one or more connected elements_ In oiher words, an activity change at any central

where Y and X are measures of rhe aciivity in two interconnected bmin regions across a sample. Since the measures are across a sample, Y and X also represent the vadance in these two regions. Equation (1) also contains the Y-intercepi for a line, d, and rhe slope of the line, B,/., indicarinS ihe size of the influence of X on y. The final rerm g is rhe residuat representing the variance in Y that is not determined b\ X Thi. represenlation i\ \implp line.r regrescion. The value of B!, is computed directly ftom the covariance of Y and X and when the measures of Y and X are standardized (transformed to z-scoies), the intercept, o, becomes zero and the slope pu, would be rhe zero-order correlation between Y and X. Equation (1) also represents ihe gdreral lineat nodel and forms Ihe foundation for almost all conventional statistical analyses from simple l-tests to canonical correlations [Harris,19751.

A simple extension of equation (1) can

represent

effects of an additional area Z on the regional activity

y=a+Bltx+u.z+,1,

(2)

the contrasting view that brain functions are the


responsibility ofspecialized areas IHorwitz and Sporns, 19941. As will be demonstrated laier, covariance analysis can coniribute more to the understanding of brain operations since it implicitly assumes that the cenrral

nervous system is a collection of parallel funciional networks rathel than segretated regions. The imporldnce of covdndnce of .1eurdl J.lrvity hai been -e(ognized by other researchers dealing with electrophysiolo$cal and imagint data lAertsen ei al., 1989, Ahissar ei al./ 1992 Gersiein ei al., 1978, Horwitz et al., 1992a1 and impliedbysome theories o{brain function lDamasio,1989, Luda,1973; Tononi et a1.,19921. Mathematical extnsion

Equation (2) represents the effets of X and Z on y The p weiShts are the degree to which these two areas influence ihe variance, or activity, of y. Because of ihe semi partiallinS of variancs sources in the compuration of the P weights, the influences of Z on y and j{ on Y are mathematically independent of each other lcohen and Cohen, 19831. Equation (2) is a multiple linear reSression. Equation (2) shows how the effcts from mulriple influences on .egional activity can be derived from looking at covariances- The equation can be further expanded io include more regions and, if expressed as matrices, can be used io define the interconnections 01 an entire neiwork. The matri)( representation is the foundation for siructuml equation models.

iil ln, r

illil.lll

The relationship between brain aieas can be de\imple linedr mdlhemali.al e\pre$ron of the variance of a region as influenced by the variance ofanother. The equation for this is:
s' ribed u\rn8 a

v:@+pv,x+{i

In equation (3), the vaiiances ofall three regions,-X, Y, and Z are represented as a vectoi that is determmecl by the weighted influence of the other regio,rb trnanx of ll weights) plus the residual influenes contained in the vector {r. The zero values in the matrix ll iepresent connections that do noi exist in the model. Equation (3) can be represented graphically, as shown in Fig

0)

Stroctoral Modelins ofBrain Inleractions.

the impact ofbrain area X and the experimental effect A (XA). The interaciion assesses whether the relationship between X and y changes because of the expeimental efJect. The B weights represent the deFee to w\kh rhe-e rhree'acro.s irnuFn,e lhe \dridn.e, or activity, of Y The influence of area X on Y, independent of the experimenial effeci, is evaluaied by the testint ihe statistical significance of pv.. The significdn.e of e\perrmenidll) relaled regional differen.e. rn Fitur l.
Graphi< representation of strucrural equarion model from equation ( | ). Cir.les reprBent the meaured variance from re8ions X. Y, ad Z. Unidirect onal arows represent the path for the inlluence of

the activity of Y, independent of th influences of region X, is assessed by evaluatinS the siFificance of


B!.,. The siSnificance of the slope Py., indicates

whether

these solrces ol vriance on each other, the weightinS of the influence given by P. CuNed bi-direcrional arrows represent

rsidua infllences whose size

is indicated

b/{.

Relationship between exprimental variance and covariance

Most of the results obtained from brain imaging studies have been derived from the analysis of the differences in regional aciivitybetween task or groups. It can easily be demonstrated thai this is the same as evaluating the covaiiance between brain activity and experimenial manipulation. Using the general linear model presented in equaiion (1), the activjty in Y is e\Pres.ed ar beinS partly determrned by an e\perimental manipulation,4.

the influence of region X changes depending on the experimental condition,i.e., whether the covariance of Xand ychanges because of ihe experimental manipulationNeuroimatint can be used to assess experiment relatd functional changes -.ritlrt brain areas by examining average activity levels and comparing ihese levels across groups or task. In eqltaiions ( ) and (5), this is represented by ihe evaluation of ihe effct of A on Y(p,/"). Funciional changesl,eh,ee, brain areas may be inferred ftom regional activity, bui some of the funciional changes may not be obvious fiom regional mean activity. For example, in eqmtion 5, ii is entirely possible for the term reprsentint the experimentally

Y=d+By"A+{,
ln this equation, y

(4)

represents a set of measures of regional activity (variance) ftom two expefmental condiiions, and A reprcsents a binary vector coding for an experimental or control condition (e.9., A = 1 for expeiimental condition. ,4 = 0 for conirol condi tion, this is also referred to as dummy coding [Pedha, zur, 1982, Cohen and Cohen, 19831). Compuiation of the influence of,4 on Y, repiesented by Py"/ indicates whethei thereis a change in the activity ofYrelated io the iwoconditions, i.e.,whetherthe mean activityof y ir different rn {he lwo condrhons. Thi\ covarian,e analysis is identical to a simple f-iest lPedhazur, 1982]. A simple exiension of equation (a) can examne experimental ffects on both regional activity and inierregional covariance.
Y=
cr

induced difference in regional aciivity (py.) to be nonsignificani, bui for the term representing the change in the relationship between X and ydue to the experimental effect (pi,") to be siSnificant. This would be missed if the covariance of X and y was not evaluated. Civen the inierconnctions among neural elemenis and that re$onal activity in the central nervous sysiem is mainly determined by ailerent influences, ihe changes in functional relationships
amongbrain regions can only be quantified by covari-

FOUNDATIONS FOR STRUCTURAL EQUATION MODELS OF NEURAL SYSTEMS

With the increasing interesi and application of


covariance-based analyses. new terminoloty has also

+ pr.x + py"A + B!,,,xA +

{,

{5)

Equation (5) represents the effect of area X on Y, the experimenial effect of A on y, and the interaction of

been introduced. It is useful at ihis point to clarify some of these terms and define their relation to the ierms we use to describe neural siructural equaiion models. The term lunctiollil colinectkns (connectiLrity) has been used to refer to the correlations of activity between neural elements in both electrophysiology lArtsen et al., 19871 and brain imaging lFriston et al., 1993b1. To say that two neural elements (neurons or brain regions) have a functional connection is to say that these elemenis show siaiisiically significant corre

Mclnlosh and Gonzlle2-Lina.

lated activity without reference to how that correlation is mediated. Efrectile con ectil,itlt is a logcal Vo Sression from functional connecti\.ity and can be defined as ihe influence or ef{ect one neural element has on another lAerisen et al., 1989, Friston et al., 1993b1. The ierm i/,r.iio,ial ]let-.ro* has been applied to the pattern of covaiances among evoked potential siies [Cevins and Cutillo, 1993], but coul.t also be applied to a patterrl of covariances obtained through other measures of neural activity. For our application ofstructural equation modeling io neural systems, we have applied ihe terms r atonidl model and futlctional model [Mclniosh and Conzalez-Lima, 1993, Mclntosh et al., 1994a1. The analonicul model simply represents the nuroanatomical connections beiween brain regions used in ihe structural equation models. The interreSional corelations ofactivity are used to assign numerical weighis to the connections in the anatomi cal model, leading io the funciional model. Afir.tio,rrl ,11od.1, therefore, represenis ihe influences of regions within the model on each oiher through the anatomical conneciions.ln some respects, the functionai model is close io ihe notion of effective connectivity since it depicts the influence of one redon on another. The difference, as will be illustrated subsequently, is that the influences in the functional model are depicted as direct and indirect effects through ihe anatomical model. Effective connections are typically not ex Pressed in this manner. There are many commercially available computer packages that are specifically designed for structural equation modeling including LISREL Ucjreskog and Sctrbom, 19891, EQS [Bentler, 1985] and AMOS IArbuckle,1992l. The algorithms used in struciural equa iion modeling have underSone some modifications since ihe initial developmeniby Wright [1920], bui the procedure remains conceptually unchanged. All structurdl equalion nodel- are de.i\ed llon co\i-id1ce matrices and from a causat structure- Figure 2 illus trates the basic processes and feaiures of structural equation models. The system, made up of four valiables, has a causal Etructure indicated by the arrows (Fig. 2A)- The regions and connections define the analomiml madel lMclntosh and Gonzalez Lima, 1993; Mclntosh et al., 1994a1. By using this anatomical model, the correlation matrix (i.e., standardized cova ances, Fig.28) canbe decomposed to assign functional wFi8hlr or y'tl4,"erf,r,"15 gr\en b) lerrer- .: .ro each of the arrows. The addition of the path coefficienis defines Ihe lunctiollal ,iodcl lMclntosh and Conzalez-Lima, 1993, Mclntosh et a1.,1994a1. The path equations (Fig. 2C) and structural equations (Fit. 2D) ar mathematically equivalent, but the structural equa-

ABC
B
D
rAB rAD

rBD

c-

rCD

/l
Path Equations

Structural

Equaiions

n -

.cD:y2

vr r vw+ yw

+yw
Figure 2.

of merhods involved in s$uctural eq!a, tion modelng of a neural ystem. A: Parh diagrm of a simple ietlvork with four bmin retions (A. B C D) and their anaromical conne.tions (iidicated by afrowq. Br The infomation about the corelations of activties between regions is used ii conjhcrion with the path diaSram (A) to calculate rhe srengrh of influen.es throuth the connections, known uthe path coefcients (v. w, L J/, z). C: Path equations show how rhe correlations between reSions can be decomposed to solve tor the path coefllcients. O: Structu6 equations show the Enan.e in acriviry in each region 6 a function ol the weighted Erlance of orher b6in reSions and a residual
influen.e (indi.ated

Schematic rep.esentaton

by{)

These residuals are

iot

shown in

Aaid

tions provide a more comprtationally efficient meihod to solve for the path coeficients as the complexity of
the system increases,

r +{
o 0

(8a)

o fAl fo ?,0

lBl =l'

v o o llc | 1,r,. lc LDI Lrz0 olLDl Lu"l


To construct a model it
iE

:I;t. lY:t

(8b)

useful to rcfer to equation

(8a and b). The model is expressed in maidx notation (8a) and expanded as vectors and matrices in (8b). The equaFon ha- a \ ector, tt, whi.h con rains rhe variancer

of re$onal activity from A ihro!8h D a matfx p, which defines the network and contains ihe path
specification is done through indicating which elements in p and {, are ri"d at zero (indicating no anatomical connection), fixed at a non-zero value, or tre io be estimaied. The zero elements ofpjn equation
coefficients, and a vector of residual efJects, {,. Model

Structural Modelins of B.ain Intractions.

(8b) represent fixed coefficienis, while the others represent coefficienis ihat are free. The vector {, is a diagonal matrix in the form presented in equation (8b). It can also be expanded to a full matrix io allow for correlations amonS iesidual influences. Solutions to ihe structural equations are typically obiained through iteraiive estimation. The mosi common form is maximum-likelihood estimahon, al' though different leasfsquares methods have been 1lsed lBentler, 1985; l6reskog and Sdrbom, 19891. Initial estimaies for ihe unknown parameters (paih coefficients and residuals) in the structural equations are obtaind and a set of implied variances and covariances arc computed llsing derivations similar to lho.e presented rn Figure 2C. The impliFd covdndnce mdln\ rs then Lompdred h rlh lhe ofltindl covananLe matrix. On the basis of the difierences between these twomatrices, modifications to parameter estimates are made usinS iierative fitting techniques (e.9., Davidon Fletcher-Powell method used by LISREL lDavidon, 1959; Fletcher and Powell. 19631, a modified CaussNewton method for EQS lBentler, 1985]). This daia fiiting procedure finishes when the differences be' tween the observed and implied covariances matrices are in an acceptabl rante. The optimizaiion routines are surprisingly wellbehaved $ven a reasonable set of equaiions and initial conditions for iterative estimation, and the methods used for iterative fitting will typically give the same results in data sets in which fte covariance matrix is not singr ar l.loreskog and Sorbom, 19891. Depariures in th final solution are likely when the numbers of known and unknown parameters aie close to being equal or there is singularity in the data set (one or more regions are perfecily related to one another). The ultimate ability of the model to reproduce the daia is given through a X, Soodnessof-fit statistic (the X,valueis the minimum value of ihe maximumlikelihood fit function, multiplied by N - 1, where Nis the total sample size Udresko& 19731).
Eflects decomposition

which residuals are included, the total effects would


be smaller than the correlation coefficient. Evaluatint influences within a system as direct, indirect, and iotal effects is known as effects decomposition and is an

important characteristic of strutural equation modeling. Ef{ecis decomposition can indicate how the influence of a region is modified ihrough indirect influ ences and whether these change dpending on the expefmntal manipulation. Effective connectivity, as

definedby Aertsen et al. [1992], resembles most closely total effects in that an ef{ective connection is the influen.e oi one neural elerrent on .nother irre<pe(tive of direct or indirect influences. In structural equation modelin& effective conneciions, or total effects. are further decomposed inio direct and indirect effects by use of the anatomical model.
Fedbak loops

One characteristic of biological neural networks is


that many anatomical connections are reciprocal. Struc-

turai equation models can solve for the functional weiShts of reciprocal connections between neural elements and show whether these loops are symmef ric or asymmetric lBerry, 1984]. Symmetric relationships have equal influences in both diiections of the loop, while a.yn'nelric reldlion\ willbe l.r8er in one direction. Such information cannot be dedved from simple paiNise correlations since coffelations are symmetric, but can be determined usint structural The abiliiy to solve these loops is relaied to ihe complexity of the system- At one extreme, ihere rs th two-region model whereby ihe regions are connecied by a loop. In this case there would be only one known quantity, the correlation coefficient. and two unknowns, the path coefficients. The system is undetermined, as there are more rnknowns than knowns. Only wiih additional information could this be solved, so ihe most parsimonious solution would be to assign each path coefficient the same value equal to half of the corielation beiween the two regions. On the other hand, an example ofa determined system is presented in FiSure 3, and explained below. ln ihis sysiem, two areas (,4 and B)are connectedby a loop, with each area receivint an additional proiection from anoiher area. There are six known correlation coefficients and four unknown path coef{icients io solve for. The added information provided by ihe
influence ofregions C and D maks it possible to solve the siruciural equation. Moreover, the estimated values foi the coefficients within the loop are not equal-

The representation of the sysiem as a set of path quations (Fit. 2C) demonsirates the ability of struciural equation models to determine dirct, indirect, and total eftects. In Figure 2, the effects of region A on C consist of the direct effect. r,, and the indirect effects through z, and y. The total of effects of A on C is the sum of the direct plus indiiect effects. The path equations depicted in Fi$re 2C do not coniain a residual term, therefore, the toial effects would be the zero-ordr correlation between,4 and C. In rne case rn

Mcln(osh and Gonzalez-Lima

(4.].---L=-a.s]l.(8)
y

/.\ il
tl

w = 0.6r

l, \
z;

=,0.6t4

tl

influences in the model, thiswouldequal ihestandardized semi partial regression coefJicieni for ihe influence of A on B, i.e., ?r. This coefficient will be differeni

-0.553

ll {ct \./
A a c D
0.48 1.00 0.52 0.16
1.00

{D) \-/
ABCD
1.00

from r,(8.), which represenis the coefficient of ihc influence of B on A, i.e., j!-, since the terms that are partialled oui of !8, namely ri. and rsL, have different valus. The standardized semipartial regression coctficieni for the influence of,4 on B (zr) is 0.616, and the
standardized semi-pariial regression coeffi.ient for the influence of B on,4 (r) is 0.397 (y = 0.552, for C on A, and: = -0.554 for D on B).'The ability to solve loops is an important feature of structural equation model ing and highlights another important concept. Looped influences can only be solved when ihe relaiionships among all regions in a model are considered simultaneously. The partialhlg procedure thai is used in structural equation modeling (and regression) reveals relaiionships ihat cannot be deduced from inierregional correlaiions.
Residual effects

0.24 .0.41 0.06 r.00

frlufe r.
AfouFregion neuralnetwork with re.iproca connections, or loop, between regionsA and I Correations coeffl.ients are siven below the neMoa, a1d tie aJes fo- each arroa a-e lhe m&irJnlikelihood estimates for the path coencients. Unlike the iitorma tion der ved from the corelaton coemcients. the path.oefrl.ients Ior the influenceswithin the loop are Aymmetnc.

The reason for this is il[rstrated


equations for regions A and B:

in the structural
(e)

Structural equation modeling aiso allows for influence. rol mFa.ured or not med-urdble lo be in\orporaied in the model as residuals [Hayduk,1987; Joreskog and Scirbom, 1979, 19891. Residual influences can be represented in at leasi two forms. One representation ofresiduals is with variable (PSl) in LISREL terminol'1, (3) and (8) and ogy and is indicaied in equations Figure 2D. These residual inflLrences are besi thought of as hcludint ihe combhed influences of regjons

,4=r:B+vC+'lr,r

B= uA+zD+VB

00)

Thoush ,4 and B both influence each other, the structural equations for each one contain additional influences that add information, i.e., the influence of re8ion C on A lequation (9)] and region D on B iequation (10)1. Since path coefficients are similar to
semi partial regression coefficienis, and since the cor relations amonS regions are not homoSeneous, the resulting path coefficients for the influence of A on B l,u) dnd B on 4 {r) will nor be equJ The l.lJ.imunr likelihood estimates for the path coefficicnts ir1 Fi8xre

outside the model and the influence of a brain region upon itself [McArdle and McDonald, 198,1, Mclntosh and Conzalez Lima, 1992ab1. It is important that residuals be allowed to occur in the model for both theoreiical and technical reasons. Bmh rgions that do not have a residual influence imltv that all ihe variance in that region is accountd iorb!'the connec-

3 illustrate this. The derivatjon of a path coefficieni relie. nn partiallin8 and \(n'i pirtiallirS or.ovirian.e. lfor a detailed expianation of pariial and semi-partial coef{icienis see Cohen and Cohen, 19831. Semi-partial coef{icienis can be obtained tfuough leasFsquarc eshmation or by using the formula for a semi partial conelahon as followsl

iions with other regiorls in ih mociel This is an


unlikely siiuation in a neurals\.sieln Formodelfittin8, fixing ihe residuals to zero forces that \ariance attrib

:r(rl resre$ion coetJicients and the rn!rtr[- i,i rh. path coefficicnb (Fig 3) are close, but not ideftriil (! rr.ir .lhei This is th result of the two
rThe

vnl!.s nrr thr -rnn

nartinrm lileilhooJ
difterent

.,- -:-

(11)

.stin .,,n r.Jhnri!e! +re.ificatly, least'squares for th rgrcsrnrn..ePirne.ri:i.j n1.r\iDum likelihood for thc path .ofti oerG Th. nrf r.:ai. rnr rh drrerenc is that th esliDales for
lean squnrrr

ln the formula, r/tsr) represents the semi-parhal correlation coefficient for regions ,4 and B with D held constant or partialled out. Wiih ihe direction of thc

narinun lLlelin!a,r
usetul to

'r'Ir,L

.nrfi.-:2r :::( leinjquars stimates ar oflen used as rs im.'.i!n nFrl ud ll m'\imln

\.r( fnirJr;:eF.rilely Ior each coefticientwhile the .: nrlri \v.r. obtaincd sinrltaneolsly. lt h

Structural Modrlin! olBruin lnteractions

uiable io residuals to be expfessed fron a sourcc within the model, r'hich can seriously impair the
ability to locate an appropriatc soluiion for the modet. PSI values in LISREL are represenied as variances and not path coefficients. They can be convertcd b a coefficient by taking its square root lLoehlin, 19871, but informaiion aboui the sign of ihe intluence (positive or negative) is not obtainable unless further model modifications arc made lHayduk, 19871. Another representation of residuals is as a variable

hrvrne " drre(l pd.h In.,ne or more .l rhe r,8inr. within the model. Conceptually, this influence would

represent a region ihat has a stronginfluence on areas within the model, but could not be included, in other words, an influence ihat is r-ms.ndrls io the lnodcl ard is unmeasured. In LISREL, exogenous variables are rcferred to as t (KSI) variables, rvhose influence can be represcnted by direct paths to the c,rdo.{?ro,ls variables

(r) in the model (ihc brain

regions

in ihe

systen).

These exogenous paths can be given a lvcighi or path

PeriPheril \en-or) urd.rn- .Lch r. ll e relrnr or,ochlea [forexamples, seeMclntosh and Gonzalez Lima, 1992a,19931.lt must be emphasized that wllile concep tually the residuai input reprcsenis a single sorr.e/ the mathematical reality is ihat other comrnon residual sources are encompassed in this hnlrcnce. As a resuli, it is not a "pure" represeniation for the single source. Esiimaiion of residual eftects wjll depend on the complexity of the model. Our typicat approach for the estimation of residuals (KSI and PSI) ls to fix these vdlue. ir 15 l. t0: of thp roral Iri.r.rce tor r gr\en brain region depending on its connections within the rnodel lMclniosh and Conzalez-Lima/ 1991, l992a,bl. Regions receivnlg more inpnis will have a lorver residual value and ior areas that do not receive influences from $'ithh the model, the efteci of residLrals is sct b 100%. These residual effects can be modified if ii significanily improves the fit of the model. Values for PSI can also be estimaied directlv as tuce parameters (but\ee simulaiion reslllis below).It is not advisable to free KSI and PSI in the \ame nodcl since there is no way to differentiate the solrrce ot the greaiest residual variance ihat leads to indeterrninacv in the final solutionStacked models for statistical comparison of structural equation modets An issue in examinnlg neural interac tions is r\lhether there is a change dependcrlt on experincntal condi-

coefticieni represented b)' I (GAMMA). Path coeffi cients amongendogenous variables are represented as B. KSIS can be useful in accounting for influences of

tions or Sroups ofsubjects (e.9., clini.al popula tion). In struciuralcquation modelin8, it is possible to conplrte the functional models wiihin cach condition and then provide a descriptive compa son of whcre the models differ [e.9., Mclntosh and Conzalez Lima, 1991]. The infereniial power of such a sirategy is, howevcr, rather limited. Most structlrral modeling programs allow for a ht ltiplt St tp or stackd nadds analysis/ where instead of estimatinS a functional model for each condition separatell,, the models are combined in a single proBram run. The process involves statistically conparing functional models, using the xr index of model fit, r4lereby path coefficienis are constrained to be equal between conditions (null model) with ihose in whicir the coetficients are allorvcd to diSer (altemn tivc nrodel). The comparison of modls is mad by subtracting the Xr value for the alternative model from the Xr value for the null model. If the alternaiive model, in which the coefficienis were allowed to differ between groups, had a significantly lower Xr value, ihcn the coefficienis ihai were allowed to vary betr\een conditions were siaiistically different. This Xj r is assessed with ihe degrees of freedom equal to ihe difference in the degrees of freedom for ihe alternative and null model. The procedure is sinnlar to a simple i-test for differences in group means in which ihe null hypoihesis is thai a single esiimate oi the mean is aclequaie for both groups (i.., the group means do not differ). For the stacked mo.lels ap, proach, th null hypoihesis is thai a single estimaie kx each path coefficient is adequate for both groups (i.e., the path coefficienis between groups do not difier). This fcature of structural equation modeling has the benfit of noi only allowing for inferential evaluaiion of different models, but also improves the statistical fiiness of ihe models b), increasing degrees of frcedom IHayduk, 19871. When models are esiimaied simultaneonsly, each covariance matrix operates as a ser of observed valucs. By constrainint certain parameters to be equal bet\^,een conditions, the ratio of knowns (obserued valuet to unknolvns (parameters to be esinnaied) is increased, making parameter identification of the modcls more likely. Measurement model tor neural systems
As of yet, an undeveloped capacity of neural sttuc

iural equaiion modelhg is the ability to account for errors of ncasurement in thc model. A complete struciural equation (Fig. 4) separates the vari, 'noclel ance ot the system inio iwo main components, a measurcment mo.iel and a siructural model lloehlin,
19871. The

measureneni model is depicied

as

thc area

Mclntosh and Gonzalellima

ey

anatomical organization. The measurement model accounts for the reliability of ihe measudng device. Such a depiction of a neural structural equation modelin8 may help to stabilize ihe estimates of the path coefficients, as it i{ould reduce the potential amount of vadance to account for. This also cleans up the sirlrctural motlel since the measurement ellor is removed from ihe residual term of the struciural model. lf a measurement model is not used, then pari of ihe residual term in the siructural model would include ihis measuremeni error.
The meanins ofa path coefficient

Fiture4.
Dtision of cohplete strLctun equation model into a mesurement and structural model. The structlral model is dep cted by e ements conta ned ir shaded Srey box. The medurement modelis those e ements oltside the box. A meslrement modelimplis that the activity obseNed in x,, and z (indicato.%riablet is a functioi
infllence of the actual act v ty of the area (X Y. and Z. atent eriablet plus some eror of medurement (<). The degree that a meaured variable reflects a atent variable is tiven b/ the valLes
or the

The technical definition of a paih coefficient (ex, pressed in terms of neural pathways) is the direct proporiional functional influence one region has on another region throu Bh iheir direct anatomical connecchanged. A paih coedrcieni

outside the greybox inFigure4 and in matrix notation


is:

[j] [i i :]l?l.l'l

i2

The measurement model represents three vaiables, t y, and z, that aie directly measured by the researcher.

These variables represent/ or ir,?i.dlc, some latent variables (X Y, and Z) that cannot be directly observed. The degree to which a lntent I'ntinblc (e.8., X) is expressed in an irdia?tor 1)l? rirble (e.9., ir) is Siven by ihe weithtinS, (e.9., I.). Since the relationships of ihe ^ and indicator variables are noi perfect, latent variabies part of each indicator variable will be composed of measurement error (., / and .). The structural model for this system was presented in equation (3). In many senses, this depiction o{a neural structural equation model tuom brain imagint data ls more accuraie, as ii implies ihat what is measured, whether ?DC or {BF, is a function of the actual re8ional d.livil) plu: \ome er-or or ned\u emenl. In mrppinS data this measurement ellor may represent everyihint from errors in quantificaiion of ducose utilizaiion or blood flow, machine drift, and recovery coefficienis, to individual dil{erences in functional and

the activity of ,4 $'ould lad to an increase of half of that unii in B; assuminS no other regions connecied to B show any change. For instan.e, ii rCBF in region A increases by i0 ml/100 I'mnl, ihen rCBF in region B would increase by 5 lnl 100 g lnin. The path coefficient indicati the a\ erage influence across the time intefval meaiurecl. If a structural equation model was con:tru.ted ior nlulti siie single neuron data, the path coeihcilnis $ ould be ihe influ, ences on a nillisecond tiIne,cal. For mtabolic mappinS daia, acti\ii\ i. tim iniegraied and is the sum of acti\ii\ h .r rpgion. Path .oefficients, in this case, sho\! the alefa{e Lniluence across that time interval. Coing ba.k tu ihe prvious example, if we measure rCBF in 1 dnd 6. thn the paih coefficient of 0.5 hdicat\ th.ri a.ross the time inte al measured (e.9., i min) the influence oi area A accounted for25% (squar of path .oerricieni) of all the innuences on B (25% of the !arian.e in B). The ph\siologr.dl interpretation of a nelral path coefficient, bried on L'rain imaginS data, is somewhat less ob\iou: in relaiion to cellular electrical eventsSince the ph\ rological inierpretation of a change in a meiabolic narker rlated io cellular electrical aciiviiy depends.n ihe Lrrdin re$on undei consideration lconzalz-Lin1.r et al., 19921, tivint a purely physiolotical interpre ia tion io a pathcoefficient is likely misleading. One imf.tation is io interpret a negaiive path

iion, irith all other regions in the model left uni, the expected change in the activitv of one region gnen a unit change in the reSion influencint it. Ii a path coetficieni for ihe influeIl:. oI retio r,{ "r B .0.r rh n r r rir incrFd.F rr

Structural Modelinc of Brain Interaclions.

coefficient as an inhibitory influence and a posiiive path coeficient as excitatory in reference to eleciro phy{oln8-cal posl<) naphl evenr-. Howe\er, rn increase in metabolism carl result from either postsynaptic excitation or inhibiiion depending on the energy demands and cellular geometry of the region [e-8., Batini et al., 1983; Hil and Scheich, 1986; Nobrega and Coscina, 1983; Nudo and Masterton, 19861. This does noi allow a direci translation of path coefficients based on metabolic mappinS data as indi ces of postsynaptic excitation or inhibiiion. This diffi, clrlty is not unique io meiabolic mapping. Similar interyretaiive difficuliies existin evoked or field potential work, in which a .hange in the electrical activity cannot be accurately inierpreted as excitaiory or inhibi tory postsynaptic activity unless additional informaiion about the specific cell populaiions recorded fuom is obtained. The pure physiological interpreiaiion of a

thebounds of the actual physiological responsewould be lost, and at woist the degree of linearity would be overestimated. However, some researchers have sug-

paih coeficient therefore depends on the activiiy nedsure- from xhi(h lhp interreSio.ldl .orariance*

If covadances between neural elements underlie brain operation, then path coefficienis may be interpreted as an indication of tunctional influences or how much of lhe ob-erved vdriance in a brdrl reSion i. due to the direci effect of an interconnected region. Here the emphasis is on whether ihe path coefficients show a change across tasks or beiween groups. If, across tasks, a path coelficient shows a large increase, or decrease, in absolute magnitude, this suggesis a quantitative change in funciional influence. If the absolute matnitude remains the same, but the sign of a coefiicient changes across iasks (e.t., positive to negaiive), this may imply a qualitative change across tasks. Dichotomies such as this are seldom complete, so it is likely that both magnitude and sign changes will ocur. When evaluated in this manner, path coefficients can indicate whether there are task- or group-rclated diflerences in functional influences within ihe same anatomical pathwaysNonlinearitis in covariance analysis
A1l models discussed so far have assumed that the relationship of the mtabolic activity between brain aras is piedominantly linear. MostbioloFcal systems, including the central nervous system, have nonlinearities in their rsponses. The implications of applying a linear model to a nonlinear sysiem, at a simple level, would be a loss of information. Ph],siological responses typically follow a sitmoidal function, which G essentially a bounded linear function. By assuming a purely linear response, information about responses at

gested that for metabolic mapping data, a linear approximation to the data is a reasonable one under most physiological conditions lFriston eI al., 7992, Nudo and Masterion,1986l. The ability to incoryorate feedback loops into structural equation models is a step towards introducing nonlinearities. More formal nonlinearities can be evaluated before modeling by examinint the sitnificance of nonlinear trends using polynomial expansions lPedhazur, 19821, and these nonlineariiies can be incorporated into the structural equation models lKenny and ludd, 19841. Ther are currently iwo mthods by which this can be done. The first involves modifyint ihe measured activity before modeling the system. and then addint an extra vari, able into the model representinS this modification- For example, if it is suspected thatre8ion yis a function of both linear effect of X and the square of the effect oft measures from X would be squared and an additional variable would be added to the model torepresent the square of X lfor examples, see Kenny and Judd, 1984 and Hayduk, 19871. The second method involves constraining the estimate of the influence of one re$on on another io b some nonlinear tunction, which could have significani utility in modelinS nonlinearoutputin response to alinearinpui. An example would be constraining the ouiput ofX (its effect on y) to be the inverse o{ the linear effect of input from vaiable Z. This feature has been incorporated into many of the pro$ams for structuial equation modeling such as EQS and newer versions of LISREL
(version 8).

SIMULATIONS FOR INCOMPLETE

ANATOMICAL MODELS
One important feature in neural structural equation modelinS is the use of anaiomical paths to define the causal structure and assess functional inieractions. The issue of the accuracy of the anatomical model and how this affects the utility of the model has not yet been e)(plored. Moreover, neural structural equation models are by necessity simplifications of reality since any given region can be influenced by numerous oiher areas, some of which may noibe included in the model. Simulations were car.ied out to provide some indication of the impact of a missing pathway and of regions ihat were noi included in the model. These simulations were Brossly oversimplified and were meant only to illustrate the behavior of the structural

Mclnlosh and Gonzalez-Lina.

equation modeling aLsorithms uncler the two co'1clitions indicated above. Methods

TABIE ll. Results from simulations*

VI
V1

v2

V3

V5

The model was construcied using EQS version 4 "regions" lBeniler and Weeks, i980; Beniler,l9ssl Six (variables V1 to V6) were simulated from a L'nii normal distribution with a samPle size of 100 (io avoid confounds due to sampl size issues lBoomsma, 19851). ln the population siruciural equaiion model, regions receiving influences from within the model had residual variances equal io 0.25, and those not receivin8 input from wiihin the model had rsidual variances sei at 1.0. The samPle .ovaiance matrix used for the analysis is presented in TabLe L Thc sPecific values tor the Dath coefficients and residuals arc siven in Table tl. itre Uase model was essentially a feectforward neiworkwith one looP between V3 and V6 A graPhic depiciion of the base model and the simlllation results is presented in FiSure 5. Three simulations were conducted to deiennine ihe effect of region or path elimination The first test moclel was an elimination of the Path from V'l to V5, the second was an elimination of V1 from the model, and the final was an elimination of the feedback from V6 io V3. The e(ects of these omissions lvere assessed by examination of changes in path coefficients from the base model and by evaluation at nlotliftoturtt n?dlccs [J6reskog and Sdrbom, 1989; HayduK 1987] Modification indices are comPuted from th firsi- and second-order pariial dedvatives for each possible parameter in the model Path coefficicnts and residuals They suSSesi Parameters thai should be freed to improve ihe fit of the model A high modification index suggesis ihai allowing the estimate of the pdrdmerer l. chdngL ru-udll) fInmzeror sould 'i8nih."ntl1 'nprove llre iil ol rhc m'd.l They cdn bL evaluated as a xr value with l degree of freedom (PSl) Udreskog and Scirbom, lgS9l Residual influences were fixed at the values obtained from ihe basc model to determine whether the most promising rmProveTABI-E L Covariance maftix used lor data simurations
V1

V2

v3
o.ror
V5

0..153

0.712

0.515
0.848

.,194

0.563

PSI
Tesi model V1

ironission ofpath from v4 to V5

1.00 1.00 0.382 0.211 0.24a

0.322

VZ
V3 o.+or

-.505

V5

0.692

1.00 PSI Test model2: omission of Vl

1.00

0.726 0.601

0.9,10

21.67

10.18

-.5rt4
0.322

0.382 0.211 0.248

V1 V2 V3
0.664
0.601

0.940

45.31

20.13

PSt
Test
V1

1.00

0.382 0.211 0.248


45

31

0.322

7.61

odel3: omission of path from V6 to V3

V2

11.46
O..ter 0.453

11.46

4.07
0.515

,u.ot

v4
V5

a_v2

,
0.248

0.489

0.374

.494 4.28 0.322 4.26

fsl

1.00

1.00

0.382
1.07

0.211

being " Each sclion conttins Path coeffici.nts Rows lnt variables afi..ted ind collnnslist sourcc ot e6ct Th. t]{o 6nal rows (PSl) show th. residual influ.n.s oneach vari.ble.ltems lortstmodek 1 :l rhorln in bold italics are thc modificatnrn indics roi ihe

crpecled improvement in th. model fit (cv.luated as itr with 1 dgree oi ireedon) if cstimate Ior thrt Parameter !{ere changed Valucs are 8r!cn for all pahncte6 lthose modification 'ndex .xceds n probability of 005 (381). Cells..nranrinS a dash ( )

indic.t. padr coeffici.nts lhal sere

sct to zero

v2

V]

V5

V6

ment to the

v] v2 v3 v.1 v5 va,

.093 1.060 -.032 -.210

0.9,t9

0.272

0.438 -.057 0.585 0.466 0.009 0.440

-.005 0.413 .146 0.386 .001 .032

1.013 0.061

increasing a residual, or adding a Path lt has been noied by other researchers that there is a iendency for unaccounted variance to be expressed in ihe residual term if the estimate for that term is unconstrarned because it is usually the fastesi way to minimize ihe fit
encesin the testmodels avoided this Possible Problem.

fit of the model woutd

come from

0..184

function lHayduk, 19871. Fixhg the residual influ-

StructuralModelinsof Brain Inreractions.

X>'l;>e \Jj/+.-\-/

9=a*

from V5 to V4 was higher than ihe modification index for the residual innuence on V5. In ihis simulation, only one missing element \\'ould have been accuratly identi6ed, the residual iniluence on V4. The residual influence on V5 would likelv have been missed since ihe modification nrder for this was lower than that of ihe path from V5 to V,1.
Test model 3: elimination of Path ftom V5 to V3 There was a reduction in the path coeficient for the infiuence of V3 on V6 (0.848 in the base model to 0.374 in test model 3) as a result of the removal of the negative feedback paih. The largest modification indices were for V6 to V3, a reciprocal pathbetween V2 to V3, and the residuals of V3 and V6 (Fig. sD). The reciprocal path likely represents an alternative way to account for the variance in V3 when ihe innuence of V6 is omitted. Though the modification indices identified the omiited path, the differences between indices were noi as $eat as in test models 1 and 2.
Conclusions from simulations

Figure 5. Ghphic depiction of results from datasimu ations to test rhe ef{ecrs of omitted paths or regions. A: 86e modelirom which the data set ws tenented. A-D: Results from three tesr hodes in which a part of the bse model wB omined. Elements that are shown by segmented lina are omissions trom rhe model, while elements hi8hllshted by a gy box ue suggsted chantes to rhe test mode s derived trom moditication indices (see text). Vaues for rhe path .oeficients. residuas, and modifi.ation indices are presented in

It appears ihat ihe modification tudices obtained from struciural equation modelinS algorithms are able to indicate possible omissions from the anaiomical
model, and where regions are omitted. Consistent with iniuition lMclntosh and Gonzalez-Lima, 1992b], omitted regions will result in increased residuals. However, the modification indices alone were noi completely accurate. In test model2, only one missing component was accurately identified, and in test model 3 the differences among indices were not as greai as in models 1 and 2. Therefore, modification indices can provide clues as to possible omissions, but the final decision ofwhether to add a path or mcrease a residual should be made by ihe researcher. Usually
the regions thatare included in the modelare selected beforehand using either sia iistical criteda or a theoreti-

Results

Test model I : elimination of po.h from V4 to Vs

In the first test model (Fi8. 5B), the estimates for the path coefficients did noi appear to change substantially. The larSest modification index was for the path from V4 to V5 and the second largest was for ihe path from V5 to V4- For test model 1, ihe modification indices accurately identified ihe missing path.
Test model 2: omission of
V

There was a large change in the path coefficient for the influence of V4 on V5 (from 0.515 in the base model to 0.995 in test model 2). This is likely a rene,lion of lhe diiempr ro jclounr Jor the !arar.e attribuiable to the missing variable (i.e., to 6t the original covariance matrix better). The larSesr modification ;ndices were for the residual influence on V,l
(PSl and influence of V4 on itself) path from V5 ro V4, and the residual influence on V5 (PSl and influence of V5 on iiself) (Fig.5C). Exarnination of the modification

indice\\u8ge\red hir aI e\tern"l innuen,e wd.mi,in8, since ihe indices for the residual influences were high. However, the modification index for ihe path

-rmuldlron.. -o therL Bill Ikply be even more in complicated neural based models. In social science applicaiions of structural equaiion modelhg, one of the main concerns is the vatidiiy of data-driven modifications ofmodels, in which it is unclearhow much of the data-driven causal struciure results from siatistical noise [Freedman, 1987, Maccallum et al., 1992]. The uniqueness of neural structurai equaiion models is less of a problem because the causal structure is estabtished by neuroanatomy. However, if modifica-

cal guide (see section on data-driven versus iheorydriven modeling presented below). There was some indeterminacy in the simplistic mo.iels used in these

MclDtosb aDd Gonzalez-Lima

.
effects- The darkness model

tions to the anaiomical modelare made from the data, the simulation results presented here sugsest that the same concerns as in social sciercc applications should extend to the neural applications.

influenc

of indirect

showed skong corticofugal effects from both VC1 and

ANATOMICAL CONSTRAINTS

ln the central nervous systcm there are numerous ways one area can have a functional impact on
another. Many neuralsystems havca parall!'l anatomical ortanization by which connections between areas can be both direct (hierarchical) and indirect. Effects decomposition of anatomically based structural equation models allows for the evaluation of whether the influence of one reSion on another is through a direct

ef{ect or is mediaied through one or more indirect routes. Moreovr, when valuatinS experimental differences, it is entirely possible for the total effects of two regions to be th same while direct and indirct effects differ, or for total effects to differ when direct ef{ects do not. An empirical examplecomes from a 2-DC siudy thai examined the effects of footshock on visual system

metabolic activity in patterned liShi and darkness IMclniosh et al., 1992, Mcintosh and Gonzalez-Lima, 1992a1. A 2-by-2 design was employed havinS a patterned light footshock condition, patterned liSht no shock condition, darkness-footshock condition, and darkness no shock condition. For full details of the study and resulis, the interested reader is referred to the primary papers. To illustrate the informaiion obtained by constraining the expression of the covariances by the neuroanatomy, portions of the functional models from patterned lighi-no shock and darkness no shockconditions will be presented. Fiture 6 shows the direct and total effects for the Seniculocortical portion of the rat visual systcm stluctural equation models. The full model contained ihe lateral posterior thalamic nucleus and thc superficial and intermediate layers of ihe superior colliculus. The Seniculocortical portion was selected to illustrate the difference between total and direct effects and how the anatomical model helps io interpret these effects. The upper poriion of the 6gure shows tirat the ascending thalamocortical direct effecis from the dorsal lateral geniculate nucleus (LGNd) to primary visual cortex (VCl) were stronSer in the patterned liSht model. Descending corticothalamic direct effecis from secondary visual cortex (VC2) were weaker in the patterned light modl,and all other direct eftects were not statistically difterent between models. Evaluation of the total effects within this iri-nodal loop (bottom of Fig.6) provided additional information about the

VC2,bui in the pattrned lightmodel, the corticofugal effects were zcro and the thalamocortical ef{ects wre relatively stronger. The differences between direct and total effects in Figure 6 suggested thai ihe indireci effects throlgh corticocortical connections and thalamocortical loops acted to chan8e the nature of thalamocortical interactions. For xample, the sign of the direct ef{ect from LCNd to VC2 was netative for the pattemed liSht model. The indirect effect of ihe LGNd would be through thc positive ascending path to VCl and the positive loop between VC1 and VC2. A positive loop tends to amplify eafects transmitted through it and therefore the indirect effeci of LCNd was large and posiiive (conversely, negative loops tend io dampen total effects). This, added to the relatively smaller neSative direct effect of LCNd on VC2, resulted in a larSe posiiiv total eftects from LCNd. Corticocortical inieractions may have acted to modify the ascending thalamic siSnal in the patterned light model. Corticai modulation of ascending signals has been documented in electrophysiological studies IMolothnikotr ei al., 1984; Wickelgrcen and Sterling, 19691. Though much of this modulaiion is likely from descendin8 corticofugal influences, the functional models shown here suggest that corticocortical interactions, especially feedback from secondary cortices, may also play an important role. Reversible lesiol experiments with cortical cooling have suggested that feedback effects ar an important determinant of prinury cortical responses [Sandell and Schiller,198]1. lvithout the use of the anaiomy as thc foundatilrn to express the interregional covariance relationships, it would noi have bcen po'srble 1,, JelermDrg ri the drfference* in the ascending efiects behleen patterned liSht and darkness models here simpl\'because of direct thalamic influences or if the\' rsulted from mediaiion through indirect eficis. The abiliiy to distinguish between direct .1nd indirect ellccts is an important quality ot structural equ.ltion modeling that sets it ,)pdrl from nlhF- L.\nr.rn(L' br\ed melhodc. The example presenied above shows that the anatomial founddtion is ihe key feature for neural struc tural equation moLiels. An immediate concern with the use ol the anaionrical constraint is the degre to which ihe anaiomic.rl model reflects realiiy. Any system of c'quations in which there are unknowns to be solved L'enc'fit lronl constraints to possible so[rtions. Usint d1e connective anatomy of the svstem helps to consirain soluiions. However, ifall m.rjor and minor paths \!re included, most models $olrlli con

Gen icu locortica I Circuits

Direct Effects Darkness

Patterned Light

Darkness

Total Effects

Patterned Light

Legeno
Positive Negative

r0.7to1.0
-At^-6
0.1 to 0.3

Schemati. of geniculocon@l luncnona mode s obiained for rars other regons. The s ze oI the dtrect or tota effect is ind <ared bI presented wth pafterned light or darkness. Modek..e presented the relative width oI the arow. Values for the width tradient are on a corona section ol the rar bran with rhe inreracling retions given in the etend the bottom ofthe f8!re Positive influences are shown d solid afows. wheres nesative ones are shown 4 shown n whte (top s do6al and rht s latera). The top vo setmeited arows. LGNd, doroal late geni.uate nu<lelsr VCl, efiects the source region on the models represenr rhe dlrect of target reSion. The boftom Mo models repretent the total effects, prima./ visual conexi VC2, s4ondarf vislalcodexwhich are rhe slms of d rect etrects and lndirect effe.B thfough

-0.41o06 Orrr.a -

Mclntosh and Gon?rle2-Llma.

tain reciprocal loops at nearlv every level, with somc interconnections beiween levcls, both feedforwarci and feedback. Whcn all possible anaionlical connectionsare includlrd, it is likclt, ihai an und('rdetermined svsten of equations would result, in which there are either the same number of known and unknown clcnrnis or morc unknown elements. In either casc, urliclue soluti(nrs are noi obtainable. A hierarchical model building strateg]' could be used whereby a smaller part of the model is estimated 6rst, th parameters fixed at those estimates, and then more pathsanci regions ad.led to complete the model [Mclntosh and Conzalez-Lima, l992al. In most cases, hor\'ever, some conrpromise between anatomical accuracy .lnd interpretability may be needecl. Any mocleling efiort, whcther ba-ed on -irnularion. ,'r ddlr-filhnt i. nece* .arly ,r rinpl6i,rliUn. and (.prc.p rl- rn dppro\im.rtion of .ealit),. It is the de8r!'e of simplification that determines th utility of th model.
STRUCTURAL EQUATION MODELING

stream started in areas 17l18, thcn went throu8h area 19d and parietal arca 7 and ended in toontal area 46. lnteractknls between the two streams were included as the an.lbmical connections be,tween areas 37 and 7, and are.1s 7 and 21. There was also a feedb.lck path inclu.led from area 46 to area 19v. The flrnctional models for the right hemisphere were consisient with the differences in nrcan iCBF. Arcas alonS the ventral stream showed stronS interactions in the object vision

IN HUMAN PET STUDIES


Siructural equation modeling of animal 2-DC studre- h-tve provideJ rmpunanr in-iBhl. Inlo br.in operntion. Recent extensions of structural equation modelin8 kr PET rCBF studis in humans havc also provided

important information beyond what was concluded from examinaiion of regional activiiy changes [Mclntosh et al., 1994a1. The nlitial application was to a visual perception study comparint cortical inier,tctions during match-to-sample tasks ior obiect visiorl (face matchinS) versus spatial vision (doClocation matching). The object visnrn task showell relativelv grcrl('r dcri\ rry rn ! enlrrl occiprtoremp.r,rl hrain drer. while the spatial vision task showed relntively greater activity in dorsaloccipital and parietal cortices lHaxby et al., 19911. Thcse results suggested a functional segre8ation of visual proccssing strearrs into dorsal and ventral patlrrvays similar to that observed in nonhuman prinrates IUnserleidcrand Mishkin, 19821. Using a principal components analysis, we were abl to identify temporal and prefronial r{rgions showing task-relaied covariance patterns. Structural equatiol models from anatomical models of dorsal and ventral processing streams were constructed for both obicct ancl spaiiat vision tasks. The brain regions includcd striaie and extrastriate area 17 and ]U, dorsal and veniral areas 19 (19d and l9v), occipibtpmporal area 37, temporal area 21, parietal area 7, and frontal area 46. The ventral stream consisted of the connections from areas 17llil, through area 19v, then into area 37 and area 21, and terminat!'d in area ,16. The dorsal

task, relltive to spatial vision, while spatial vision funciional models showed stronSer interactions along the dorsal strean. Structural equation modeling extendcd the results by showinS how processing follo$'ed into temporal and lrontal cortices. The models added to the results by showinS ihat these iwo sireans were not functionally independent as there rvere strong inieractions beiween them in both conditions. Also, the el{ects of ftontal lobe fedback were task dpcndent, where feedback was present only in the spatial visior model. Within the same anatomical Drodel, the left hemisphere tunctional nrodels did not show the separation ofprocessing streams present in the riSht hcmispher. This seemed contrary to the activation results, which showed equal activation in boih hemispheres. It was hypothcsized that the bilatral activation may have arisen from transcallosal influences of the risht hemi sphere on the left lHorwiiz et al., l992al. Interhemi' spheric siructural equation models showed that this hypothesis was tenable. As illustrated schemaiically in Fiture 7, ventral arcas in the riSht hemisphre had strongtr contralateral influences than did the lcft hemisphere areas. In thc spatial vision models, dorsal areas showed sinilar asymmeiric inflLlences. These aslrmmetries could only have bepn deduced from the
covaflance analyses, Wc have recently extended ihe objct vision models to look at changes in this basic functional neiworkin a

delayed maich-to-sample iask in which th delay interval was paramctrically increased. In this study, we werlr able to rcplicate the oriSinal obiect vis'on network, and we showed chan8es in both right hemisphere and left heDlisphere interaciions as a function ofincreasing delay IMclntosh ct al., l994bl. Across the delay interval, the functional models showed a dc' crease in ihe right hemisphere inieractions along the veniral stream with strongef interactions among dorsal areas into cingulate cortcx, and bilateral increased interactions arnong frontal, temporal, and cingulate areas. Collectirelv, the resrlts from thse stLrdies show that the aPplication of struciura I equatior nodelinB to brain ilnaging in hnmans will Sreatl), aid in thc

. Stru.lur.l

Modelire ofBraitr Interacdons.

Object Vision

Spatial Vision

as<-

46

46

aa

19vi
17

19v t18

Inte.hemspherlc ilnctona mods for obiect vGion and spatal nte.hem spher c nteractions n both rsks. The magnitlde ol the vison taks (see tex9. Brodmann ares are shown on a schematc d rect efiect s iidcated by the relat ve wdth of rhe atrow. The ora hor zonta sect on ofthe human bm n Gop is anteror. afd rert is va ues for the width gradient are $ shown in Fisure 6. Posir ve eft within each section). More doEally ocated are6 7 and l9d are nf uences are shown s solid arrows. wheres neSative ones are separated by gay boxes. The fi8ure llsrates the dymmet.c shown 6 segmented arrows.

intcrprctation of the distributecl ictiYity ch.lnges un, derlving cognitive opcrations.


DATA.DRIVEN VERSUS THEORY-DRIVEN
MODELING A concern with image based analyses is (41etheL an

equation modeling is t),picallv thought of as a confirmabD'.pproach (confirmaiory factor anaLysis) sin ce a

or discul timed lLoehlin,1987l. A purely data-driven appronch requi.cs adclitional staiistical methods to construct a structural modI.
causal modcl is uslrally bcing confirmed Thcsc nrcthods arc used to select regions that apPear to be operating as n functiolal Lrnii. Some examPlcs

objcctivc or clata-driven mcthod is superior to a purcly thcoretic.l approach. Thi\ h.s been an rssue rn
the anal],ris of l'ET daia and is demonsh.atcd by ihc intcreslbased (theoretical) approaches Ie.9., ',. fox t al., 19i18 verslrs Peiit ct al., 19931. A snnilir clisiinclnrn can be nade in covariancc analyris and is oilcn disiin, guisheclasexploratory (objcctive) \'eLsLrsconfirnaiorY

drhFrpr"p.n p\ts1-b,\.., ,bi,, .p.

r.

-' -

.,n.,i

in.lude the use ol univariate analyses of reSnrnal actiYity beir{en condition, (e.8., t iesis, ANOVA), or.
oihcr multivariate methods such as l'CA (and deriva, ti!e5) nncl discriminani analysis. Univariate ditfer, ences in reSional activity can provide clues for somc regions that need to be includcd h a struciural cquati.rn nodel. PCA based on ihe covariances btseen brain arcas sunrnrarize the potentinlly large covariance nairices from the comrnon patierns oi relauonlhips amont brain regions and suSsesi regi(nls that mat, be part oi ditferent functional systems.

'rh,1',ur('l Jr.,l\-,. fr r,ipal .,rrrpor err.-acah-i.

(IrCA) and fack,r analvsis arc e\reniiailv exploratory techniques since no constrainis afe placcd up hou' the variance in the sysicnr is xpresse.l. Shuctural

clnro\h and Gonzalez-Limn

This approach has been used in PET iCBF stndies of visual perception to select retions for a structural equaiion model lMclntosh et al., 1994a,b]. A further

seldom useful in practice. Therefore, rather than assumin8 a posture ateither end of the continuum, it is more

extension of this, discriminant analysis, selects weighted combinations of retions that differcntiate experimental conditions and serves as an indication of the functional systems that distinguish cond;tions. Discriminant analysis has been used for the selection of relevant reSions for inclusion in a model in a brain mapping study of associative learnint [Mclntosh and Conzalez-Lima, 19941. Other groups have also used principal componenis analyses, but not in the context
of build ing structura I equation models IGoldenberg et al., 1989, Lagrize et al., 1993, Moeller and Strother, 1991; se also papers by Friston and Alexander and Moeller in this issuel.

productive to amalgamate qualities of both objective and theoretical approaches in to covariance-based modeling efforts. This represe^$ a data-dtutn bttt hypothcsisco,.5trniill,r] ltpproach to modeling. For experimental conditions in which the functional systems involved
are noi obvious, a data-driven approach can be adopted to select brain areas usinS such methods as a PCA or

Daia-driven approaches can be confounded by


sample-specific conditions that limit the generalizability of the results. Forexample, heterogeneou s samples, outlier observations, and measurement error can all influence covariances within a sample. All analysis algorithms cannoi distinglish these sources of variance and therefore they may be expressed in what appears to be strong changes in covariance. Principal components anaLysis may be especially vulnerable since it simply summarizes the covariance matrix and therefore if some of the observed covariance patterns

are a result of noise, they will be reflected in the principalcomponents IWidaman, 1993]. Theory-driven approaches usually eniail ihe selection of a "system of interest" befor the experiment. This was the approach used in our initial application ofstructural equation modeling to functional neuroimaSint studies of the rai auditory and visual systems lMclntosh and Gonzalez-Lina, 1991, 1992a1. The theory-driven approach is used when specific hypotheses are being tested about the nature of a Particular neural system. For example, the choice of the auditory system was ddven by ihe hypothesis that functional interactions in the auditory system could code for the behavioral significance of acoustic stimuli as well as the pure physical characteristics IMclntosh andConzalez-Lima, 199L, 1993l.'N hile the same potential statistical prcblems with sample-specific chaiacteristics can affect theory-driven models, a maior concern with theory-driven approa(hes is whether the actual functional models for a given iask are ideniified. It is possible that the system of interest does not show a chanSe in the o(periment and that the functional model is actually composed of anotherset of regions. As with most dichotomies, distinctions such as da ta-d riven versus theory driven are uselulin discussing seemingly opposinS views or approaches but are

discriminant analysis alonS with univariate regional analyses- Structural equation modelinS can provide cllres as to possibLe functional influences (i.e., paths) thatshould be added to the model toimprove explanatory power. The data-ddven approach should be constrained by whether the functional influence can theoretically exist whether there is an anatomical conneclion belwFen reSrons. For e\ample. cuppo:e in modeling the cortical visual system there is a large modification index fora onnection from striatecortex to prefrontal cortex. Since there have been no reports of direci striatofrontal connections, this path would noi be included. This may be taken as a case in which theinfluenceismediatedbyindirectconnections(e.9., occipito-temporal frontal) and suSgests that another region should be added to the model. E)amples ofthe data driven theory-constrained approach are in FDG experiments dealing with Pavlovian conditioning in rats lMclntosh and Conzalez-Lima, 19941 and in human PET rCBF studies of visual perception and memory [Mclntosh et a1.,1994a,b]. This combined approach has an additional benefit in developing theodes of brain operation. Because each structural equation model combines empirical data with researcher intuition it forces ihe models to be explicitly descibed. Each anatomical connection needs to be confirmed. Any connections that are included without specific reference to neuroanatomy (e.9., effective connections) need concrete theoretical explanation as io whether the effective conneciion is mediated through brain areas not included in the structural equation model. Neural structural equation models add a degree of exactness that is not often present i)l brain imaginS siudies. With the ability of brain imaging to measure activity through ihe entire brain it is often the case that numerous areas show increases or decreases in activity in an experiment. Brain imaginS researchers will often discuss the results in terms of "functional neiworks" without specific references to how these network are formd. By requi'in8 that the nelworki be e\pressed In a covari ance-based model, the assumptions of the researcher as to the organization of the neiwork are more easily

Structural Modeling ofAmin Inte.rctions.

The relative exactness of neural siructural equaiion models also allows for the generation of testable hypotheses. The functional models obtained from struciural equation models of the human cofiical visual system showed that feedback tuom prefronial cortex was present in a match{o-sample task involving spatial locatior! but not in ihe matching of faces lMclntosh ei a1.,1994a1. This led to the hypothesis that the involvement of feedback from the prefrontal cortex depends on the task difficulty. Moreover, rn.ne face-matching task there was a stronger influence of the right hemisphere on left hemisphere than the left hmisphere on the ritht. This led to the hypothesis that the right hemisphere was ensaged in most of ihe taskand ihatleft hemisphere involvementwas through callosal influences. Our research on associaove redrrr in8 involvint Pavlovian condiiioning of auditory stimuli in the rai lMclniosh and Gonzalez-Lima, 19941 has suggesied ihai the sign (positive versus netativ) of the influences within a basal forebrain loop involvingthe septalregions and the nucleus accumbens may reflct ihe moiivational or affective property of the acoustic stimulus. The associative value, on the other hand, may have been refle.ted by interactions within a limbic thalamocortical circuit of retrosplenial, perirhi nal, and insular cortices and the antedor thalamus. The value of structuial equation modeling as a data analytic tool for brain ima8in8, and as a hypothesisgenerating hypothesis-testint tool has been discmsed. There is anoiher potential role for neural structural equation models as a bridge between xpedmental data and nural networkmodelingboth at the sysiems and neuronal level Isee Horwitz and Spoms, 1994, for a full discussion of these issuesl. Here, the functional models can act as constraints for computational models based on reSional interactions lotto ei al., 1992] or neuronal interactions lTononi et a1.,1992]. This potential will greatly expand the theoretical utility of siruc tural equation modeling in neuroscience.

tor reSiondl dclivr.y Junng tdsks of inlerest (e.9.. electrophysiology). On ihe other hand, if the covariance among neural elements is criiical to brain operabehavior must b viewed in ihe contexi of its interactions wiih other regions. Network analytic approaches have supported the idea that brain function involves the cooperative interaction among many neural re gions, and though it may be that a particular area is citical for a certain function, the performance of any task is a result of the funciional interactions of many regions llohn and Schwartz, 1978; Conzalez-Lima, 1992, Mclntosh and Gon zalez Lirna, 79931. The study of neural interactions will be important for relating cognitjve theodes with brain operations. It is highly unlikely that ihe functional organization of rhe brain follow. lhe rndependeni moduldr orgdni./dtion of psycholo$cal construcis. Therefore, it is also

tion, the role of any $ven region in a particular

unlikely that a single brain re8ion has only one co$itive function. lnstead, fhnctionally specialized anatomical networks within the brain mav be more
easily related io cognitive constructs. There may not be a single brain area that represents "aitention" for instance, but there are more likely numerous brain areas whose intractions represeni atteniion operations. The imporiant point is that it may be possible for parts of the same anatomical network to be involved in anoiher function when the interactions change. For example/ numerous behavioral brain studies have su8gested that primary auditory areas show activity related both to ihe pereptual components of a stimu-

WHAT IS THE BENEFIT OF ANALYTIC APPROACHES TOWARD THE STUDY OF NEURAL INTERACTIONS IN NEUROSCIENCE? Many contemporary cognitive neuioscience theo ries are based mainly on evidence obtained concerning the role a particular structure plays in a particular behavior. For example, researh on memoryhas dif{erentiated between those memory piocesses thai are "hippocampal dependent" and "hippocampal inde pendent" IEichenbaum et al., 1992, Squire et al., 19931. These theoies incoryorate data from animal lesion studies, human clinical studies, and studies tna! monr,

lus and its learned behavioral relevance lconzalezLima, 1992, Mclniosh and Gonzalez-Lima, 1993, Scheich ei a1.,1992; Weinberger et al., 19901. Thus, the same anatomical network can code, in parallel, the perceptual and behavioral properties of stimuli dependingon the nature of the interactions between the parts of the network. The hippocampus has a wellestablished role in declarative memory piocesses lsquire et al., 1993], but its activity has also been related to voluntary moior behavior and sensory processing in high states of arousal lBland, 1986, Sainsbur), et al., 19871 and habituation or motivation Icray and McNaughton, 1983; lanard, 19931. These examples sutgesi ihat different brain areas can play important roles in multipl functions beyond their classical distinctions, and ihis may be a teneial properiv of the ceniral nervous system rather than specific ro orl\ d few brdin retion.. Indeed. lhFse viesr dre consistent with ihe adaptive characieristics of the .L rtrcl nervous -v-rem. in whrch tun,lionrl orSanird-

Mclnlosh and Gonzalez-Lima.

tion is viewed as dynamically related to the Particular environmenial demands rather than a static proPerty Uohn and Schwartz, 1978; Mclntosh and Conzalcz

Boonena A (1985): Nonconv.rgcnce, improper solutions, and starting valus in LISREL maimum likclihood estination. Psy
chometry50:229 212
Cohen l, Coh.n P {1983): Applied Multiple Rgression/Cotrelation Enbaunr Associates DaDrario AR (1989) Th biain binds entitiesand cvenh by nultire Bional adivation lrom convergn.e roncs. Nural ComP 1:123
132

Lima, 1993, 1994; Merzenich and Sameshima, 1993, Pascaul-Leone et al., 1994; Recanzone ei al., 1992, Sheich ei al., 1992, Wolpaw and Lee, 1989t Zohary et al., 19941. Brain imaginS iechniques will make an important contribuiion to the understanding of this propefiy/ given their ability to assess activity across many neural regions. Covariance analyses like strx.iural equation modeling will contribuie to th1s understanding by determining the functional relahons among these areas and showing how they are modrfied JeppndinB on lhe behd\io al coqnrtr\e requirF-

Analvsis lor the Bhavnrral Scienccs Hillsdale, NJ Lawren..

Davidon WC (1959): Variable MetricMethod for Minimizalion. AEC Re..arch and Development Report, ANL5990. ArSonn, lL: Argonne National Laborato!y Eichenbaun H, otto T, Coh.n NJ {r992): Th hippocanp$: what docs it.lo? Beha! NeuralBiol5T:2 36.

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ACKNOWLEDGMENTS
The authors thankDr. Barry Horwitz and Dr' Nancy

Cereb Blood Flow Mtab 8:6.12-653.

Lobaugh for their insishtful discussions rn the preparation of ihis manuscriPt. We acknowledge suPport for this work toom NIMH grant R01MH43353 and NSF grant IBN9222075. A.R.M. was supported by ihe Natural Sciences and Engineering Research Council of

l.

FreeJm.n DA (1987): As otheN se. u!: A .ase studyin Path nnalysis J EducStat 12:101 128. tiiston KJ, Frith CD, Liddl PF, Fiackowiak RSJ (1991): ComParinE iunctional (PET) imaEesi The a$essnnt or siSniticant chan8 .l Cercb Blood Flos Metab11:690 699. Friston KJ, Iriih CD, Liddle Pf, liackolti.k RSJ (1992): Motor pra.tic..nd nurophysiologicnl adnPtationin thc.f.bellunr A positron mission tonograPhv sludr" Prc. R Soc Lond lBioll

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