Development and Psychopathology, 14 (2002), 653–666Copyright 2002 Cambridge University PressPrinted in the United States of AmericaDOI: 10.1017.S0954579402003139

Levels of analysis in etiological researchon schizophrenia

TYRONE D. CANNON AND ISABELLE M. ROSSOUniversity of California, Los Angeles

AbstractEtiological research spanning domains of inquiry as diverse as social psychology and molecular genetics hasidentified a number of potential factors that likely contribute to the development and clinical manifestation ofschizophrenia. In this article, we first highlight the challenges inherent in developing cogent etiological models thatrepresent both the diversity of suspected causal influences and their mechanisms of action. Then, using our ownresearch program as a heuristic context, we present a general analytical framework for identifying and integratingmultiple types of etiologic factors across different levels of analysis in the prediction of schizophrenia. Inrecognition of the myriad complexities of multifactorial causation, we argue that a multilevel causal perspective isrequired for the development and advancement of a fully nuanced theory of schizophrenia etiology andpathophysiology.

In schizophrenia, as in other domains of psy- havioral outcome but do not necessarily oper-ate via precisely the same mechanisms. Thechopathology, research has revealed a diver-

sity of factors thought to represent causative challenge for psychopathology researchers isthus to specify etiologic models that integrateinfluences (e.g., Cannon, 1997; Carlsson, 1995;

Cohen & Servan–Schreiber, 1992; Karayior- putative causal influences across multiple lev-els of analysis (Carpenter, 1987; Engel,gou & Gogos, 1997; Selemon & Goldman–

Rakic, 1999). In some cases these factors de- 1977). The primary goal of this article is todescribe an analytical framework for such in-rive from the same general domain of inquiry

(e.g., anatomical brain lesion and altered neu- tegration. In so doing, we provide a concep-tual overview of work conducted in our labo-rotransmitter function), and in some cases they

derive from quite disparate domains (e.g., so- ratory and elsewhere as it relates to a multilevelperspective on the etiology of schizophrenia.cial cognitive and biological influences). In

either case, such findings imply multifactorialcausation in which the various causal influ-

Typology of Causal Influencesences ultimately coalesce in producing a be-

It is important to recognize at the outset thatmost forms of psychopathology are complexly

The research described in this article was supported bydetermined phenomena, whereby multiple caus-grants from the National Institute of Mental Healthal influences that may be separated in time(MH52857 and MH48207), Theodore and Veda Stanley

Research Foundation, and March of Dimes Birth Defects and place and distinct in terms of mechanismFoundation, and by gifts from the Rutherford Charitable of effect, integrate in the determination of aFoundation and the Staglin Family. (not necessarily static) behavioral endpoint (Cic-

Address correspondence and reprint requests to: Ty-chetti & Tucker, 1994). In considering therone D. Cannon, Department of Psychology, Universityways in which two or more causal influencesof California, Los Angeles, 1285 Franz Hall, Los

Angeles, CA 90095; E-mail: cannon@psych.ucla.edu. may be integrated, it will be heuristic first to

653

T. D. Cannon and I. M. Rosso654

review concepts and terminology with regard sufficient but nevertheless participate causallywhen present; such influences are said to beto causal influences per se.

A critical dimension along which causal contributing causes. In psychopathology, mostdistal causes are likely to be contributing in-influences vary is spatiotemporal proximity to

the behavioral endpoint in question. In psy- fluences; these may derive from quite dispa-rate domains of inquiry or levels of analysischopathology research we are typically inter-

ested in both distal and proximal causal influ- (e.g., stressful life events, cognitive schema,inherited predispositions). In some cases, aences, because understanding both will be

critical for developing a complete model of number of distal factors will be causally re-lated to a behavioral endpoint via a final com-etiology and both may present targets for ther-

apeutic or preventive intervention (Cicchetti mon pathway or mechanism. In the above par-lance, such a mechanism would be considered& Cannon, 1999). The distinction between

distal and proximal causes is closely related a proximal sufficient cause.It must be kept in mind that we are rarelyto that between the terms etiology and patho-

physiology in the field of medicine (An- in a position to measure putative causal influ-ences directly. Rather, we measure indicatordreasen, 1987). Whereas distal causes typi-

cally refer to types of influences (e.g., genes, variables or markers of factors or processesthat are suspected to be causal. In a multileveltoxic exposures, etc.) that represent funda-

mental initiating processes relevant to disease framework, we could be investigating multi-ple indicators of the same fundamental causaletiology, proximal causes typically refer to

the mechanisms through which distal causes process but from different perspectives, or wemay be investigating multiple different causalachieve their effect on the behavioral endpoint

(e.g., neuronal loss). As we shall see in the processes that interact in complex ways. Wewill generally be in a position to know whetherexamples to follow, developing a framework

for understanding the relationship between a particular indicator or marker variable is,strictly speaking, causal, and if so, its mannerdistal and proximal causes of psychopathol-

ogy will typically involve adopting a multi- of causal relation to the behavioral endpoint,only after extensive investigation in whichlevel perspective on disease causation, as the

distal and proximal causes will generally dif- other interpretations of its role (e.g., as epi-phenomenon) have been ruled out. An indica-fer in their mechanism(s) of causal effect in

relation to the behavioral endpoint; that is, tor variable that is in itself not causal maynevertheless be quite valuable in etiologic re-they will more often than not derive from dif-

ferent levels of analysis. search; for example, such a variable may bemore directly or reliably assessed than theAnother dimension along which causal in-

fluences vary is in terms of their degree or causal factor or process that it marks.frequency of causal relation to the behavioralendpoint. In genetics this concept is expressed

Multilevel Causationin the term penetrance (Bodmer & Cavalli–Sforza, 1976). Some causal influences are al- Multilevel causation is implied whenever two

or more causal influences exert their effectsways present in the histories of patients witha particular form of psychopathology and on a behavioral endpoint via different mecha-

nisms. There are at least four ways in whichmay, on that basis, be considered necessarycauses. Some causal influences are present this causal integration may be achieved: sum-

mation, transduction, interaction, and cascade.only among patients with a particular illness(though not necessarily in every case) and are, These concepts are, of course, already famil-

iar in etiologic research on psychopathology;on that basis, considered sufficient causes (cf.,Cicchetti & Aber, 1986). A causal influence the descriptions given subsequently empha-

size their meanings and utility in regard to thethat is present in all cases of an illness, andonly among individuals with that illness, is integration of causal influences across levels

of analysis. It is important to keep in mindboth necessary and sufficient. Finally, somecausal influences are neither necessary nor that more than one of these forms of multi-

Etiology of schizophrenia 655

level integration may apply with respect to a achieved. In this example, the particular CNSchanges encoded by the “disease genes” are atgiven behavioral endpoint, as will become

clear in a later section, in which we consider least proximal sufficient causes of the geneticcomponent of the trait variance, but they maya multilevel perspective on the causes of

schizophrenia. not be strictly necessary for at least somecases of the disease phenotype. Likewise, al-though the relevant disease genes may be suf-

Summationficient for producing the CNS changes thatlead to the behavioral endpoint, there may beTwo or more causal influences may affect the

behavioral endpoint independently via differ- many other, nongenetic causes of suchchanges among the population of affectedent proximal mechanisms (e.g., Maziade, 1988).

In this circumstance, their causal effects in re- cases. It is also important to note that no formof psychopathology is under complete geneticlation to that endpoint are additive (i.e., their

joint occurrence does not have a larger causal determination, so a model specifying exclu-sively the genetic component of a diseaseimpact than the sum of their independent in-

fluences). This mode of integration may be phenotype is, in this context, necessarily in-complete.relatively common in psychopathology, in

which behavioral endpoints are often definedin terms of groupings of multiple symptoms

Interactionand signs, the causes of which may differ. Tothe extent that the different symptoms or di- The causal influences of two or more factors

on the behavioral endpoint may depend onmensions of an illness phenotype are deter-mined independently, by different causal fac- their mutual occurrence. This form of causal

integration would seem necessarily to applytors, the influences of these factors areintegrated additively with respect to determi- to many forms of psychopathology in which

a particular environmental event or conditionnation of the overall phenotype. This form ofcausal integration may apply, for example, in is implicated but not all individuals exposed

to that event or condition develop the illness.explaining positive and negative symptoms ofschizophrenia, cognitive and vegetative symp- Some form of prior vulnerability or predispo-

sition would seem to be required to explaintoms of depression, and so forth.this selectivity of effect. In some cases, therequisite vulnerability may have been acquired

Transductionvia prior environmental risk exposures. Suchan interaction is suspected to play a role inSome (typically distal) causal influences are

transduced into proximal mechanisms of be- the etiology of major depression, in whichstressful events (e.g., the death of loved one)havioral effect. Genetic influences on behav-

ior are examples of this form. A behavioral sensitize the brain’s stress responsivity sys-tems, resulting in a lower threshold for theendpoint that is under partial genetic control

is not encoded directly by the genes that con- subsequent activation of these systems (Heim& Nemeroff, 2001). Although both the initiat-tribute to the trait variance. Rather, such

genes encode specific proteins that operate via ing event and the subsequent stressors derivefrom the same domain of inquiry (i.e., socialparticular biochemical pathways. In the case

of psychopathology, the relevant genes most cognitive influences), their effects on the ill-ness phenotype may depend on their proximallikely affect pathways related to central ner-

vous system (CNS) structure, physiology, interactions with neurohormonal mechanisms,and vice versa. In other cases, the predispos-and/or function. The genetic contribution to

the behavioral endpoint in question is thus ing factors with which environmental risk ex-posures interact may be inherited. In this case,transduced via its effects on the CNS. It is

important to emphasize that the evidence of the “character” encoded for by the gene prod-ucts is not the disease phenotype per se but asuch transduction does not necessarily mean

that a complete etiologic model has been trait or traits that confer vulnerability to par-

T. D. Cannon and I. M. Rosso656

ticular types of environmental events or con- table (Cannon, Kaprio, Lonnqvist, Huttu-nen, & Koskenvuo, 1998; Kendler & Diehl,ditions.1993). The familial recurrence pattern ofschizophrenia is not attributable to Mendelian

Cascadedominant or recessive inheritance of a singlemajor gene (Risch, 1990). Rather, the bulk ofInfluences at different levels of analysis may

occur as sets of cascading influences, where epidemiological evidence points to polygenicinheritance, whereby multiple genes of smalla particular causal influence is transduced or

otherwise integrated into another causal influ- effect contribute to increasing risk for the dis-order but only result in its overt expressionence, which in turn is transduced or otherwise

integrated into a third influence, and so on if their combined effects cross a hypothetical“threshold of liability.” It is possible that dif-(cf., Cicchetti & Tucker, 1994). In this case,

an influence occurring early in the cascade ferent combinations of such genes may beconducive to schizophrenia, a situation re-may or may not itself continue to be an active,

operative cause of the behavioral endpoint. ferred to as genetic (or locus) heterogeneity.Further, some predisposing genotypes may beCertain of such influences may become “fixed,”

traitlike features that are necessary for disease transmitted without an expression of the clini-cal phenotype (Cannon, Zorilla, Shtasel, Gur,vulnerability but do not participate directly in

symptom formation. Integration of causal in- Gur, Marco, Moberg, & Price, 1994; Gottes-man & Bertelsen, 1989). Such a genotypefluences via cascades is intrinsic to the con-

cept of development. Cascades are also com- may be necessary, but, at least in some cases,it is not sufficient for overt schizophrenia;mon in neuroscience models as the effect of a

particular initiating event (e.g., cell depolar- nongenetic influences must then also partici-pate. Some of the most prominent nongeneticization) sets off a chain reaction involving

electrical, chemical, and structural changes influences thought to play a role in schizo-phrenia occur during gestation and birth andbefore it is expressed in behavior.are thus separated from onset of the clinicaldisorder by some 15–20 years (Cannon,

A Multilevel Perspective1997). Putative causal influences more proxi-

on the Etiology of Schizophreniamal to the expression of clinical symptoms in-clude disturbances at many different levels ofIn the remainder of this article, we will at-

tempt to apply the concepts and terminology the nervous system, such as structural volu-metric changes, anomalous receptor distribu-of multilevel causation outlined above to a

number of issues in etiologic research on tions, and disturbed functioning in severalbrain regions (Cannon, 1996; Harrison, 1999).schizophrenia. The issues highlighted herein

were chosen from among the domains of our However, some of these changes also havebeen observed in the nonsymptomatic first-own research program that may be of heuris-

tic value in the context of a discussion of lev- degree relatives of patients with schizophrenia(e.g., Cannon et al., 1994), indicating that theels of analysis. Although this overview pro-

vides relatively broad coverage of the causal changes can participate in symptom formationonly indirectly. Some may be secondary toinfluences thought to play a role in schizo-

phrenia and their possible modes of integra- the disease process or its treatment, and somemay be epiphenomena. It thus remains ambig-tion, this overview is not intended to be ex-

haustive in either respect. uous which of the neural disturbances inschizophrenia are necessary or sufficient forThe first question to consider is, what is

known about the etiology of schizophrenia disease expression, which of these featuresare under the control of which gene(s), andthat indicates that different causal influences,

operating through different mechanisms, are under what circumstances and in what mannernongenetic influences also play a role.likely to be involved? Genetic epidemiologic

studies have demonstrated that schizophrenia This complexity necessitates a strategy thatis capable of separating neural features associ-is substantially, although not completely, heri-

Etiology of schizophrenia 657

ated with an inherited susceptibility from ences on behavior are not expressed directlybut rather must be transduced into behavioralthose involved in disease expression and that

permits the evaluation of a candidate neural propensities by means of effects on the CNS.Our strategy has therefore focused on eluci-system across multiple levels of analysis si-

multaneously. That is, we require a frame- dating neurobiological and neuropsychologi-cal correlates of genetic predisposition thatwork for determining how the putative proxi-

mal mechanisms of schizophrenia derive from could be used as phenotypic indicators in link-age studies. This approach represents an ex-its distal primary causes and how the different

types of distal and proximal influences co- plicitly causally integrative strategy, as we areevaluating indicators of putative mechanisticalesce in their mechanisms of behavioral ef-

fect. In the paragraphs that follow, we attempt processes mediating between distally caus-ative genetic factors and behavioral pheno-to illustrate how a multilevel causal perspec-

tive may inform etiologic research on schizo- typic expression. Such “endophenotypic” mark-ers are more proximal to the mechanism ofphrenia in three major domains: gene localiza-

tion, the isolation of nongenetic influences, gene action than clinical diagnostic categoriesand should thus be more sensitive to variationand the elucidation of neural mechanisms.in underlying genetic determinants than clini-cal diagnosis. In particular, such indicators

Gene localizationshould index the degree of genetic liabilityamong both affected and nonaffected familyAttempts at isolating specific genes that con-

fer vulnerability to schizophrenia have thus members in linkage studies (Cannon, 1996;Gottesman, McGuffin & Farmer, 1987; Holz-far been only moderately successful (Moldin,

1997). Of the handful of positive genetic link- man, 1992).Promising endophenotypic indicators forage findings, only a few (e.g., on chromo-

somes 6p, 8p, and 22q) have been replicated schizophrenia include disturbances in the pre-frontal and temporolimbic systems and theirin independent samples, and the linked region

spans a relatively large chromosomal segment interconnections. Impairments in these sys-tems are relatively prominent against a back-(~5–10 cM) in each case (Karayiorgou &

Gogos, 1997). Efforts to locate and character- ground of generalized cerebral dysfunction(Cannon, van Erp, Huttunen, Lonnqvist, Salo-ize specific genes that confer vulnerability to

schizophrenia have been hindered by a num- nen, Valanne, Poutanen, Standertskjold–Nor-denstam, Gur, & Yan, 1998), and individualsber of factors, most notably the lack of means

to identify nonpenetrant gene carriers and un- with acquired lesions in these areas show manyof the symptoms characteristic of schizophre-certainties concerning the extent of genetic

heterogeneity. In principle, these issues might nia (Luria, 1980; Roberts, Done, Bruton, &Crow, 1990). Further, similar impairmentsbe resolved by including subthreshold diagno-

ses that are associated with schizophrenia in have been observed in a portion of the non-schizophrenic first-degree relatives of schizo-family studies (e.g., schizotypal personality

disorder) in the definition of affection status phrenics, suggesting that such measures maymark the presence of a genetic diathesis to theand by performing linkage analyses in subsets

of families sorted into discrete groups based illness. However, it remains to be determinedwhether this familial aggregation reflects heri-on certain clinical features of index cases. In

practice, broad versus narrow designations of table (rather than shared environmental) influ-ences, and if so, whether there are two or morephenotypic affection status have been observed

to have little effect on linkage statistics, and independently heritable dimensions of dys-function. To address these issues, we recentlydifferences in the overt clinical characteristics

of index cases such as the type and severity applied a comprehensive neuropsychologicalbattery to representative samples of monozy-of symptoms do not appear to be useful in

defining subgroups of families that segregate gotic (MZ) and dizygotic (DZ) twins discor-dant for schizophrenia and demographicallyparticular (sets of) predisposing genes.

As discussed previously, genetic influ- similar MZ and DZ control twins (Cannon,

T. D. Cannon and I. M. Rosso658

Huttunen, Lonnqvist, Tuulio–Hennrikkson, we found that OCs associated with fetal hy-poxia, but not nonhypoxic OCs, predict an in-Pirkola, Glahn, Finkelstein, Hietanen, Ka-

prio, & Koskenvuo, 2000). We found that per- creased risk for schizophrenia in adulthood(Cannon, Rosso, Hollister, Bearden, Sanchez,formance deficits on tests of spatial working

memory, divided attention, intrusions during & Hadley, 2000; Rosso, Cannon, Huttenen,Huttenen, Lonnqvist, & Gasperoni, 2000).verbal memory retrieval, and choice reaction

time were correlated within discordant MZ Further, in both cohorts, the effect of hypoxia-associated OCs on risk for schizophrenia re-twin pairs and were associated with degree of

genetic loading in the cotwins of schizophren- mained significant, even after accounting forthe occurrence of nonhypoxic prenatal influ-ics (i.e., MZ > DZ), both independently of

each other and of deficits in general cognitive ences.Fetal hypoxia and other OCs probably doability. Additionally, patients performed worse

than their MZ cotwins on tests of verbal and not cause schizophrenia on their own, becausethe vast majority of people exposed to suchvisuospatial declarative memory but not on

the liability-related measures. These findings complications do not become schizophrenic(Cannon, 1997). Rather, the majority of thesuggest the partially independent genetic de-

termination of deficits in at least four cogni- evidence points toward a model whereby ge-netic and environmental factors combine ei-tive domains in schizophrenia patients and

their relatives. A question of major impor- ther additively or interactively to influencedisease liability. The additive model predictstance for future work is whether the different

sets of predisposing genes and associated en- that both an increase in the number of diseasegenes (or lack of protective genes) and an in-dophenotypic traits, operating via at least par-

tially distinct neural pathways, summate or crease in the number or severity of OCs arecapable of independently increasing the liabil-interact in the determination of overt schizo-

phrenia. ity to schizophrenia. In the genotype–environ-ment interaction model, one or more predis-posing genes must be present in order for OCs

Isolation of nongenetic influencesto increase disease liability. Consistent withthe interaction model, we have found thatAre nongenetic etiologic factors capable of

causing schizophrenia on their own, or do OCs are associated with an increased risk forschizophrenia in the offspring of affected par-they contribute to liability only in concert

with genetic factors? If the latter is the case, ents but not in the offspring of normal controlparents (Cannon, Mednick, & Parnas, 1990;then how do the genetic and nongenetic influ-

ences aggregate together? A nongenetic con- Parnas, Schulsinger, Teasdale, Schulsinger,Feldman, & Mednick, 1982). However, thesetribution to schizophrenia must exist in light

of the fact that roughly one-third of MZ cot- high-risk studies do not exclude the possibil-ity that OCs have a direct influence on diseasewins of schizophrenics are not affected with a

schizophrenia spectrum disorder (Cannon et liability that is simply too small to detectwhen liability is expressed as the presenceal., 1998). Of the various environmental fac-

tors proposed to be involved in schizophrenia, versus absence of clinical diagnosis. Never-theless, it should be possible to determineobstetric complications (OCs) have shown the

most robust association (see Cannon, 1997, whether genetic factors and OCs contribute in-dependently or interactively to disease causa-and McNeil, 1988, for reviews). When spe-

cific types of OCs have been examined, both tion by comparing quantitative indicators ofliability among individuals with and withoutdirect and indirect measures of fetal hypoxia

have emerged as the strongest predictors, oc- a genetic background for schizophrenia andwith and without a history of OCs (i.e., as in acurring in a larger proportion of patients than

exposure to infections during gestation and fe- factorial analysis of variance design; Cannon,Gasperoni, van Erp, & Rosso, 2001).tal growth retardation (Cannon, 1997). In our

recent work with two birth cohort samples, In a series of studies, we found evidence

Etiology of schizophrenia 659

supporting the genotype–environment interac- significant pattern in siblings. In contrast,there were no differences in any of the volu-tion model in relation to neuroanatomical

markers of schizophrenia. For example, in an metric measurements of low-risk control sub-jects with and without hypoxia.early study using computed tomography, the

contribution of OCs to ventricular volume was If OCs participate causally in schizophre-nia, then why are their neurally disruptive ef-found to scale with an increase in genetic risk

defined according to whether neither, one, or fects separated in time from the onset of diag-nostic symptoms and signs by some 15–20both parents were affected with schizophrenia

spectrum disorders (Cannon, Mednick, & Par- years? Although we can only speculate as tothe mechanism(s) involved in the timing ofnas, 1989; Cannon, Mednick, Parnas, Schul-

singer, Praestholm, & Vestergaard, 1993). More schizophrenia onset, a prominent candidatemay be the rate of cortical synaptic “pruning.”recently, we examined the magnetic reso-

nance images of schizophrenia probands, their The latter is a developmental elimination ofsynapses that peaks around late adolescenceunaffected full siblings, and demographically

matched control subjects without a personal or in the prefrontal and association cortices(Feinberg, 1982; Huttenlocher, 1979; Kesha-family history of treated psychiatric morbidity

(Cannon, van Erp, et al., 1998; Cannon et al., van, Anderson, & Pettegrew, 1994). Interest-ingly, this late neurodevelopmental process1998; Cannon, van Erp, Rosso, Huttunen, Lonn-

qvist, Pirkola, Salonen, Valanne, Poutanen, coincides with the period of peak risk for theonset of schizophrenia. In light of this tempo-& Standertskjold–Nordenstam, 2002). Both

schizophrenic patients and their full siblings ral contiguity, some investigators have pro-posed that schizophrenia arises due to exces-exhibited significant reductions in frontal and

temporal lobe gray matter volumes and signif- sive pruning, such that a reduction of neuronalsynapses below a certain threshold producesicant increases in frontal and temporal lobe

sulcal cerebrospinal fluid (CSF) volumes, psychotic symptomatology (Feinberg, 1982;Keshavan et al., 1994; McGlashan & Hoff-compared to controls, independently of the ef-

fects of age, gender, and whole brain volume. man, 2000). Within this framework, varia-tions in the rate of synaptic pruning wouldVentricular CSF volume increase and white

matter volume reduction, however, were found vary the age of clinical onset of schizophre-nia. Interestingly, excessive pruning is consis-in schizophrenics but not their unaffected sib-

lings. This pattern of results suggests that tent with several brain abnormalities docu-mented in schizophrenia, including prominentfrontal and temporal lobe gray matter reduc-

tions may reflect the influence of genetic (or reductions in neuropil volume (Selemon &Goldman–Rakic, 1999), pyramidal dendriticshared environmental) factors while ventricu-

lar enlargement and white matter deficits ap- spines (Garey, Ong, Patel, Kanani, Davis,Mortimer, Barnes, & Hirsch, 1998), and syn-pear to be specific to the clinical phenotype

and may therefore reflect the influences of aptic protein levels (Glantz & Lewis, 1997).Furthermore, because synaptic pruning in-unique environmental factors (or factors sec-

ondary to illness expression). Subsequent volves predominantly glutamatergic synapses(Keshevan et al., 1994), exaggerated pruninganalyses examined fetal hypoxia as a possible

intervening environmental mechanism under- could result in glutamate receptor hypofunc-tion, which is a possible cause of striatal do-lying some of these abnormalities (Cannon et

al., in press). We found that the temporal lobe paminergic hyperactivity and psychotic symp-toms in schizophrenia (Csernansky & Bardgett,gray matter and sulcal CSF volumes of pa-

tients and siblings exposed to fetal oxygen 1998; Grace, 1991; Olney & Farber, 1995).We have proposed that the neurotoxic ef-deprivation were smaller than the temporal

lobe gray matter volumes of those who were fects of hypoxia-associated OCs may reducethe amount of synaptic pruning required innot. Hypoxia also appeared to be differen-

tially related to increased ventricular CSF in late adolescence to cross the psychosis thresh-old, leading to an earlier age at onset of schizo-the patients, and there was a similar but non-

T. D. Cannon and I. M. Rosso660

phrenia among individuals at risk (Rosso et ing of irrelevant stimuli or maintenance of agoal directed line of thought. A number of in-al., 2000). In support of this hypothesis, the

temporal lobe brain regions that are particu- vestigators suggested that these strategic defi-cits reflect a failure to utilize contextual infor-larly vulnerable to fetal hypoxia (Volpe, 1995)

also have been consistently implicated in mation to guide ongoing behavior (Cohen &Servan–Schreiber, 1992, 1993; Gray, Feldon,schizophrenia (Cannon, 1996). Thus, hippo-

campal neurons are reduced in number or Rawlins, Hemsley, 1991). Early attempts toevaluate this context-processing deficit modeldensity following fetal hypoxia (Kuchna,

1994; Yue, Mehmet, Penrice, Cooper, Cady, utilized classical and incidental learning para-digms that could also be applied in rodents.Wyatt, Reynolds, Edwards, Squier, 1997), as

they appear to be in the schizophrenic brain These studies yielded results suggesting thatsome schizophrenic patients, like animals with(Falkai & Bogerts, 1986; Jeste & Lohr, 1989).

These cellular findings are consistent with the experimentally induced lesions producing hy-peractivity in the mesolimbic dopamine sys-in vivo data from our laboratory as summa-

rized above, indicating an association between tem, fail to show the inhibition of learning ex-pected to result from preexposure to the testfetal hypoxia and temporal gray matter defi-

cits in both schizophrenics and their unaf- stimulus in a different context (Buhusi, Gray,Schmajuk, 1998). More recently, Cohen andfected siblings but not in comparison to sub-

jects at low genetic risk for schizophrenia Servan–Schreiber (1992, 1993) operational-ized context processing as an aspect of work-(Cannon et al., in press). Preschizophrenics

with a history of fetal hypoxia may therefore ing memory. In this model, an internal repre-sentation of context is maintained in workinghave a lower baseline number of neurons and

synapses in the temporal brain regions than memory and utilized by executive processesin the strategic allocation of attention andthose without such a history. With this re-

duced neuronal reserve, less synaptic pruning other processing resources.In neuropsychological studies, while schizo-due to normal or aberrant developmental pro-

cesses during adolescence would be required phrenic patients have been found to show per-formance deficits on nearly all measures ofto cross the psychosis vulnerability threshold,

resulting in earlier clinical onset in individuals functioning, against this background of gener-alized deficit, working memory, attention, ab-with the schizophrenia genotype. In the termi-

nology of multilevel causation, the effects of straction, learning and memory, and languagefunctions appear to be more severely affectedthe distal nongenetic influences are first trans-

duced into a fixed vulnerability trait (i.e., de- (e.g., Saykin, Gur, Gur, Mozley, Mozley, Res-nick, Kester, & Stafiniak, 1991; Saykin, Shta-creased cortical synaptic density), that is, by

itself, not of sufficient severity to provoke sel, Gur, Kester, Mozley, Stafiniak, & Gur,1994). Working memory dysfunction might insymptom formation. Instead, this distal vul-

nerability trait interacts with normal or aber- fact underlie performance deficits in otherdomains such as abstraction, attention, andrant neuronal maturational processes later in

life, more proximally to the onset of disease language, because covarying measures of theformer tends to eliminate patient-control dif-expression, as part of a developmental cas-

cade. ferences on the latter (Condray, Steinhauer,van Kammen, & Kasparek, 1996; Gold, Car-penter, Randolph, Goldberg & Weinberger,

Elucidation of neural mechanisms1997; Stone, Gabrielli, Stebbins, & Sullivan,1998).Several lines of evidence suggest working

memory and the dorsolateral prefrontal cortex More direct evidence of involvement of theprefrontal cortex in schizophrenia comes from(DLPFC) in particular as a potential locus of

dysfunction in the pathophysiology of schizo- functional and structural neuroimaging stud-ies. Although the observation of hypoactivityphrenia. At the descriptive level, schizophre-

nic patients appear to have a basic deficit in of prefrontal cortex at resting baseline insome patients is not highly reproducible andstrategic processing, such as inadequate filter-

Etiology of schizophrenia 661

may be secondary to medication and/or chro- man–Rakic & Selemon, 1997). Several neu-ropathology studies have reported increasednicity effects (Ingvar & Franzen, 1974;

Weinberger & Berman, 1996), there is consis- prefrontal neuronal density along with de-creased thickness of the prefrontal cortex intent evidence that schizophrenic patients fail

to activate DLPFC to the degree seen in nor- schizophrenic patients (Benes, McSparren, Bird,SanGiovanni, & Vincent, 1991; Davis &mals when performing the Wisconsin Card

Sort Task (WCST; Rubin, Holm, Friberg, Vi- Lewis, 1995; Selemon, Rajkowska, & Gold-man–Rakic, 1995, 1998), and a negative find-debech, Andersen, Bendsen, Stromso, Larsen,

Lassen, & Hemmingsen, 1991; Weinberger, ing (Benes, Davidson, & Bird, 1986) has beenattributed to methodological weakness (Wil-Berman, & Zec, 1986). In a functional neuroi-

maging study of MZ twins who were discor- liams & Rakic, 1988). These alterations areproposed to reflect a neuropil deficit, an inter-dant for schizophrenia, the affected twin ex-

hibited less DLPFC activation during the pretation that is consistent with findings of re-duced pyramidal spines (Glantz & Lewis,WCST than their cotwin in each of the 10

pairs (Berman, Torrey, Daniel, & Weinberger, 1997), decreased synaptic protein levels (Garey,Ong, Patel, Kanani, Davis, Hornstein, &1992). Only one functional neuroimaging

study has thus far appeared employing specif- Bauer, 1995; Glantz & Lewis, 1995), and in-creased cell membrane catabolism (Keshavan,ically a task of working memory in schizo-

phrenic and control subjects. It showed that, Pettegrew, Panchalingam, Kaplan, & Bozik,1991; Pettegrew, Keshavan, Panchalingam,once the movement artifact was eliminated,

patients were found to show less activation in Stychor, Kaplan, Tretta, & Allen, 1991; Wil-liamson, Pelz, Mersky, Morrison, & Conlon,DLPFC on functional magnetic resonance im-

aging during maintenance of verbal material 1991). Moreover, increases in neuronal den-sity are particularly pronounced in corticalin working memory (Callicott, Ramsey, Tal-

lent, Bertolini, Knable, Coppola, Goldberg, layers where pyramidal neurons receive dopa-minergic inputs (Selemon, et al., 1998) andvan Geldern, Mattay, Frank, Moonen, &

Weinberger, 1998). extend glutamatergic projections (Selemon, etal., 1995), suggesting a reduction of pyrami-At the structural–anatomical level, schizo-

phrenic patients show a variety of volumetric dal dendritic and axonal arborization. In lightof evidence that dopamine D1-receptors pref-changes throughout the brain, including re-

duced cortical, hippocampal, and thalamic erentially localize to pyramidal spines anddendrites, a loss of these receptors secondaryvolumes and increased sulcal and ventricular

volumes (Pfefferbaum & Marsh, 1995). Re- to neuropil deficit would be expected inschizophrenics (Goldman–Rakic & Selemon,cent neuroimaging work indicates a relatively

greater degree of reduction in the frontal and 1997). In fact, a recent PET investigation ofD1-receptors in schizophrenia found signifi-temporal cortical volumes compared with the

posterior cortical volumes (e.g., Cannon, van cantly decreased binding in the prefrontal cor-tex of neuroleptic-naıve and medication-freeErp, et al., 1998b). Interestingly, global and

dorsolateral prefrontal volumetric deficits patients (Okubo, Suhara, Suzuki, Kobayashi,Inoue, Teresaki, Someya, Sassa, Sudo, Mat-have been found to correlate with perfor-

mance deficits on tests sensitive to working sushima, Iyo, Tateno, & Toru, 1997). Nota-bly, D1-receptor reduction predicted negativememory processes (i.e., executive, attentional,

and context-based recall tests; Maher, Man- symptomatology and working memory im-pairment.schreck, Woods, Yurgelun–Todd, & Tsuang,

1995; Seidman, Yurgelun–Todd, Kremen, Neuroreceptor studies have also providedpreliminary evidence of cortical glutamatergicWoods, Goldstein, Faraone, & Tsuang, 1994).

It was recently suggested that a reduction of hypofunction and enhanced striatal dopaminerelease in schizophrenia. Cortical glutamater-interneuronal neuropil underlies findings of

prefrontal volume reduction in schizophrenia gic insufficiency is corroborated by threelines of evidence: (a) there is a report of in-and results in the hypoactive dopaminergic

modulation of pyramidal cell activity (Gold- creased gene expression of N-methyl-D-aspar-

T. D. Cannon and I. M. Rosso662

tate (NMDA)-receptor subunits in the pre- pathophysiology of schizophrenic symptoms(Breier, Adler, Weisenfeld, Su, Elman, Picken,frontal cortex of schizophrenics, a possible

compensatory response to glutamatergic Malhotra, & Pickar, 1998; Carlsson, 1995;Grace, 1991; Olney & Farber, 1995). Inhypofunction or receptor loss (Akbarian,

Sucher, Tafazolli, Trinh, Hetrick, Potkin, schizophrenia patients, significantly higherthan normal striatal synaptic dopamine releaseSandman, Bunney, & Jones, 1996); (b) results

from receptor density studies, while variable has been demonstrated in vivo following am-phetamine administration (Breier et al., 1997;across brain regions, are consistent in demon-

strating an upregulation of glutamate receptor Laruelle, Abi–Dargham, van Dyck, Gill,D’Souza, Erdos, Krystal, Charney, & Innis,binding in the frontal cortex of schizophrenic

brain tissue (Deakin, Slater, Simpson, Gil- 1996).The question that naturally arises in thischrist, Skan, Royston, Reynolds, & Cross,

1989; Nishikawa, Takashima, & Toru, 1983; context is whether there is a differentialcausal role of abnormalities in this brain areaSimpson, Slater, Roynston, & Deakin, 1991;

Toru, Watanabe, Shibuya, Nishikawa, Noda, at the different levels of analysis (e.g., struc-tural, physiologic, cellular, molecular). Devel-Mitsushio, Ichikawa, Kurumaji, Takashima,

Mataga, & Ogawa, 1988), with one report of oping an answer to this question rapidly be-comes extraordinarily complex. On one hand,unaltered prefrontal non-NMDA glutamate re-

ceptor binding (Healy, Haroutunian, Powchik, there would appear to be a natural hierarchyof effects such that behavior depends on phys-Davidson, Davis, Watson, & Meador–Wood-

ruff, 1998), and (c) there is evidence of re- iology, which in turn depends on structure, inwhich case it may be reasonable to considerduced presynaptic glutamatergic function in

schizophrenia, including increased frontal the structural changes as having causal pri-macy. On the other hand, altered physiologyglutamate uptake (Deakin et al., 1989), re-

duced frontal levels of glutamate (Tsai, Pas- of this region may be a sine qua non for psy-chotic symptom formation, and this alteredsani, Slusher, Carter, Kleinman, & Coyle,

1995), and decreased NMDA-mediated gluta- physiology may be achievable, with psychoticconsequences, by means other than structuralmate release from synaptosomes of postmor-

tem samples of prefrontal cortex (Sherman, neuronal changes (e.g., altering cellular inter-actions). Although in principle these alterna-Davidson, Baruah, Hegwood, & Waziri,

1991). Together with evidence that cortico- tives could be segregated by conducting sta-tistical tests of mediation, ambiguity is likelystriatal glutamatergic projections modulate

subcortical dopamine release (Carter, 1982; to remain due to intrinsic differences in preci-sion of measurement and specificity or prox-Grace, 1991; Kaliva, Duffy, & Barrow, 1989;

Karreman & Moghaddam, 1996; Monaghan & imity to the mechanism of behavioral effectbetween the measured constructs from the dif-Cotman, 1985; Sesack & Pickel, 1992; Ta-

ber & Fibiger, 1993) and that the systemic ad- ferent levels of analysis. Further, in some situ-ations, the relationship between abnormalitiesministration of ketamine and other NMDA-

antagonists enhances extracellular dopamine across levels of analysis may be inextricablybidirectional, in which case no single levelconcentration (Verma & Moghaddam, 1996),

resulting in focal activation of the prefrontal may ever be deemed as having causal primacy(Cicchetti & Cannon, 1999). It is tempting incortex and perceptual distortions in healthy

volunteers (Breier, Molhatra, Inals, Weisen- such situations to conceptualize the abnormal-ities as “opposite sides of the same coin”; thatfeld, & Pickar, 1997) as well as symptom ex-

acerbation in schizophrenic patients (Lahti, is, as different perspectives of the same phe-nomenon.Holcomb, Medoff, & Tamminga, 1995; Mal-

hotra, Pinals, Adler, Elman, Clifton, Pickar, The above discussion engages the possiblecausal significance of one particular brain re-& Breir, 1997), these findings support the

hypothesis that a primary NMDA-receptor gion in schizophrenia, namely, the prefrontalcortex. Of course, we already know that dam-insufficiency gives rise to hyperactive sub-

cortical dopamine neurotransmission in the age to this area, by itself, is not sufficient to

Etiology of schizophrenia 663

produce enduring psychotic symptoms. The is further compounded for schizophrenia, adisorder whose distal causes predate its mani-DLPFC probably contributes causally to

schizophrenia, but its causal role is unlikely festation by decades and whose proximal pre-dictors may result from the synergism of theseever to be understood in isolation. The com-

plex behavioral phenomena of schizophrenia initiating factors with subsequent neurodevel-opmental and/or psychosocial influences.are simply not tractable to a traditional lesion

model. Progress in this area depends critically Based on the foregoing, we have proposedthat a multilevel causal perspective is requiredon the development and testing of multisys-

tem models in which we evaluate the modes for the development and advancement of afully nuanced theory of schizophrenia etiol-of causal integration among multiple affected

brain systems. ogy and pathophysiology. Within the contextof our own research, the application of thisintegrative strategy has shaped a conceptualframework that incorporates the interaction ofConclusionsdistal (i.e., genetic risk, fetal hypoxia) andproximal (e.g., gray matter reduction) predic-The multifactorial etiology of schizophrenia

presents psychopathology researchers with a tors of schizophrenia across multiple levels ofanalysis. In light of our findings to date, theproblem that, thus far, has been difficult to

unravel. Identifying individual causative in- resultant differentiation of vulnerability anddisease related indicators holds considerablefluences entails the disentanglement of a mul-

tiplicity of genetic and nongenetic factors in- promise for the specification of genetic fac-tors, nongenetic influences, and neural mech-teracting in unknown fashion and manifesting

effects at levels of analysis spanning the mo- anisms in the etiology and pathophysiology ofschizophrenia.lecular through the behavioral. This challenge

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