Structural Asymmetries of the Human Brain and Their Disturbance in

Structural Asymmetries of the Human Brain andTheir Disturbance in Schizophrenia

fry Richard Q. Petty

Abstract

Asymmetries of the brain have been known about forat least a century, but they have been explored indetail only relatively recently. It has become clearthat, although different asymmetries are commonthroughout the animal kingdom, they are mostmarked in the human brain. Disturbances in asymme-try are particularly striking in patients with schizo-phrenia and perhaps all psychotic illnesses, and mayprovide the neurological substrate for the etiology andclinical manifestations of the illness.

Key words: Structural asymmetries, functionalasymmetries, laterality.

Schizophrenia Bulletin, 25(1): 121-139,1999.

The two hemispheres of the human brain and their inter-actions have intrigued scientists and philosophers for cen-turies. Although functional asymmetries—the simplestbeing handedness—have been known for millennia, it isonly within the last 150 years that it has gradually becomeclear that there are also structural differences between thetwo sides of the brain. However, as recently as 1929, acomparative study of endocranial casts (endocasts) ofmodern and prehistoric man and of anthropoid apes foundno marked cerebral asymmetries (Weil 1929). Until rela-tively recently, it was usually held that only humansexhibited structural asymmetries, but increasing evidenceindicates that structural lateralization is common amongsuch disparate nonhuman species as birds, monkeys, andapes (for a review, see Bradshaw 1991). Furthermore,there is impressive evidence that structural asymmetriesare to be found far back in evolution: studies of a 600-million-year-old Cambrian fossil, the calcichordatePlacocystites forbesianus—a primitive forerunner ofsome vertebrates—appear to show clear evidence of cau-dal asymmetry (Jefferies and Lewis 1978). Indeed, it maybe that asymmetry is the rule. However, it is also clearthat the greatest degrees of structural laterality are to befound in the human brain. Presumably, this increase in

the degree of asymmetry is what misled earlier investiga-tors to think that asymmetry of the nervous system wasnot present in other organisms. (Other asymmetries—forinstance, one claw of the blue crab being larger than theother—have long been known.) It has also become clearthat asymmetry is not found only in the cortex, but also inmany subcortical structures, presumably reflecting theirclose interrelationships.

The apparent ubiquity of cerebral asymmetry amonganimal species raises a number of important questions, adetailed discussion of which lies outside the scope of thisarticle. Similarly, we must omit an exploration of the pos-sible reasons for these asymmetries. For the interestedreader we recommend a recent review by Lent andSchmidt (1993).

The objective of this article is to examine the currentevidence concerning the normal structural asymmetries ofthe brain, then move to a discussion of the disturbances ofthese structural asymmetries in schizophrenia. While thisreview deals with the evidence concerning structuralasymmetries that have been revealed by neuroimaging, innormal individuals and in those with schizophrenia, thedata must clearly be placed in the broader context ofasymmetries discovered from other sources, includinganatomy, paleontology, and biochemistry. We would alsostress at the outset that the unbridled enthusiasm of the1970s for unequivocal differentiation of hemisphericstructure and function has given way to an appreciation ofthe fundamental reciprocity between the hemispheres(Gruzelier 1981; Nass and Gazzaniga 1989; Efron 1990).

Gross Anatomical Asymmetries

The developing brain already shows marked asymmetriesby the second trimester of pregnancy. The cortical fissuresare consistently found to appear earlier in the right hemi-sphere (Dooling et al. 1983; Nowakowski 1987), and the

Reprint requests should be sent to Dr. R.G. Petty, 10th Floor, GatesBldg., University of Pennsylvania Hospital, Philadelphia, PA 19104.

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Schizophrenia Bulletin, Vol. 25, No. 1, 1999 R.G. Petty

most marked asymmetry in the brain, that of the planumtemporale, has been identified in fetal brains (Wada et al.1975; Chi et al. 1977) and in the majority of infants(Witelson and Pallie 1973). This structure is of greatimportance in health and perhaps also in schizophrenia.

The earliest studies of structural asymmetries of thebrain concentrated on indices such as the weight and vol-ume of the hemispheres, the relative proportions of grayand white matter, and the differences in the thickness andfolding of the cortex on the two sides. Perhaps because ofthe limited technologies employed, few differences werefound. However, there were some reports of reproducibleasymmetries. Eberstaller (1884) and Cunningham (1892)both described asymmetries in the posterior ends of theSylvian (lateral) fissures, the left reaching further backand being more horizontal. These findings have beenconfirmed using arteriography (LeMay and Culebras1972) and computed tomography (CT) scanning (Rubenset al. 1976; LeMay and Kido 1978). It has also becomeclear that the distribution of this asymmetry is related tohandedness (Hochberg and LeMay 1975).

Before these contemporary confirmations, it had beenassumed that the longer left Sylvian fissure was a conse-quence of larger temporal and parietal opercula, whichform, respectively, the floor and roof of the posterior fis-sure. This was partially confirmed by Pfeiffer (1936),who demonstrated a larger left temporal operculum.Additionally, he made the observation that the left planumtemporale (PT) was larger on the left The PT is a trian-gular area lying on the superior surface of the superiortemporal gyrus, between Heschl's transverse gyms (theprimary auditory area) and the most posterior portions ofthe Sylvian fissure. This finding was confirmed in elegantstudies that also showed the left PT to be larger on the leftside in 65 percent of brains, approximately equal in 24percent and larger on the right in 11 percent (Geschwindand Levitsky 1968). This distribution of PT asymmetryhas since been confirmed many times (Teszner et al. 1972;Witelson and Pallie 1973; Wada et al. 1975; Kopp et al.1977).

With the advent of sophisticated neuroimaging tech-niques, it has proven possible to identify the PT on mag-netic resonance imaging (MRI) scans, and once again theasymmetry has been confirmed (Steinmetz et al. 1989),together with the new observation that the relative dimen-sions of the PT on the two sides are related to handedness(Steinmetz et al. 1991; Barta et al. 1997). The left PT maybe as much as 10 times larger than the right, greater thanany other asymmetry anywhere else in the human brainand far outstripping any asymmetries observed in otherspecies so far examined. There are other differences in thePT on the two sides, the most striking being the existenceof one or more additional transverse gyri (Pfeiffer 1936;

Campain and Minckler 1976). These findings have beenconfirmed in the fetus: The PT develops between the 29thand 31st weeks of gestation (Chi et al. 1977),

There is ample reason for taking a special interest inthis region of the brain. Not only is it the most highly lat-eralized so far identified, but it also contains a portion ofthe heteromodal association cortex responsible for thecomprehension and generation of language (Galaburda etal. 1978, 1987, 1990; Galaburda and Sanides 1980;Leinonen et al. 1980; Galaburda 1993). This same systemis involved in a number of other major cognitive func-tions, including working memory (Mesulam 1985;Goldman-Rakic 1987, 1990). The PT is also the typicalsite of injury in patients with Wernicke's aphasia.

Taken together, these observations suggest an inti-mate association between the anatomical asymmetry ofthis discrete region of the brain and the functional local-ization of much language activity to the left hemisphere.Attention has also been drawn to the incidence of asym-metries of the PT and the incidence of hand skill in thepopulation (Annett 1992). It is of note that similar asym-metries in this region have been identified in the chim-panzee (Yeni-Komshian and Benson 1976). One majorproblem remains, however, that is of general importancein any discussion of sizes and volumes of structures in thebrain. It is the problem of generating a precise definitionof what constitutes the PT. This point has recently beenexplored in some detail (Galaburda 1993; Barta et al.1995).

In the frontal lobe, the size of the regions involved inlanguage are, in both fetal and adult brains, paradoxicallysmaller in the left hemisphere than in the right, if meas-ured only according to the visible surface area (Wada etal. 1975). However, over a century ago, Eberstaller(1884) noted that regions around the frontal operculum, acomponent of Broca's (the anterior language) area, aremore convoluted—hence, probably larger—on the left.These findings have received support using contemporarymethodologies (Falzi et al. 1982).

A number of other asymmetries have been noted inthe brain, particularly through the use of radiologicalmethods. Furthermore, the study of "endocasts"—theimpression that the brain leaves on the inner surface of theskull—has made it possible to make inferences about theshape of the brain of ancient man and nonhuman anthro-poids. Thus it has become feasible to make deductionsabout the evolution of cerebral dominance. This is signif-icant, because the structural organization of the brain is ofgreater importance than just its size (Holloway 1968).The endocast of a Neanderthal dated at approximately50,000 years old showed the pattern of Sylvian fissureasymmetry characteristic of modern man (Boule andAnthony 1911; LeMay and Culebras 1972). More re-

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Structural Asymmetries of the Human Brain Schizophrenia Bulletin, Vol. 25, No. 1, 1999

markable still is a similar finding in Peking Man datedover 500,000 years ago (Shellshear and Smith 1934). Ifwe remember that the common explanation for the differ-ences between the two sides is that it resulted from thegrowth of areas of the brain responsible for language, apossible implication is that language may have developedearlier in evolution than is normally assumed(Kochetkova 1978).

There are no clear effects of ethnic origin on brainasymmetries (Hrdlicka 1907). In a study of 297 EastAfrican skulls, the right frontal and left occipital regionsof the brain protruded beyond the corresponding struc-tures on the opposite sides (Gundara and Zivanovic1968). These protrusions are known as petalias. Themost characteristic pattern, a more protruding right frontallobe, is termed right fronto-petalia. It is typically associ-ated with a greater protrusion and width in the left occipi-tal lobe—left occipito-petalia. This protrusion in normaladults is a reflection that the left occipital lobe and theright frontal lobes are larger than their counterparts in theopposite hemisphere (LeMay and Kido 1978; Pieniadzand Naeser 1984). This is referred to as "counterclock-wise" or "Yakovlevian" torque, and it is most marked inright-handers. These characteristics are certainly presentat 32 weeks gestation (LeMay 1984) and are reflected ingross volumetric measures of the frontal and occipitalregions (Weinberger et al. 1982). In studies of the brainsof early humans, it appears that this characteristic patternwas also present 100,000 years ago.

The most marked asymmetries of the cerebral hemi-spheres are found posteriorly. This is the major compo-nent of the normal torque. Associated with this is usuallya greater protrusion of the outer margin of the left occipi-tal bone, compared with the right (Smith 1907). In asso-ciation with this greater left-sided posterior extension, theipsilateral thalamus and choroid plexus (when it can beseen due to calcification of the glomus) also lie posteriorto those on the right (LeMay 1976). The left occipitalpetalia is associated with a more posterior positioning ofthe splenium, longer temporal horn, and cerebellar protru-sion, all on the same side (Hadziselimovic 1980). Sincethe early part of this century, attempts have been made torelate the shape of the head, and particularly of the petal-ias, to handedness (Smith 1907, 1908), but with only lim-ited success. The development of progressively moresophisticated methods of analyzing MRI data (e.g., Falket al. 1991) is revealing a number of patterns that appearto be typical. In addition to the now familiar counter-clockwise torque, there appears to be a leftward asymme-try of the temporal back of the caudal portion of the infra-Sylvian surface. This is balanced by a rightwardasymmetry of the parietal bank (Loftus et al. 1993). Thepattern can be best visualized in three dimensions as a

"balanced asymmetry" in the horizontal plane. Apartfrom the association of the normal torque pattern andhandedness and the "balanced asymmetry," other grossmorphological asymmetries are associated with somemeasures of functional asymmetries, notably speech later-alization and handedness both in vivo (Ratcliff et al.1980) and at postmortem (Witelson 1983; Witelson andKigar 1992).

Similar asymmetries are also seen in apes and to alesser degree in some monkeys (LeMay 1976; Hollowayand De La Coste-Lareymondie 1982). In a study of pho-tographs of 28 higher apes, the human pattern with ahigher right Sylvian fissure was present in 16 and thehigher left in only 1 (LeMay and Geschwind 1981).Similarly, an examination of ape and monkey endocastshas shown that the apes resemble humans, as, to a lesserextent, did Old World monkeys. However, there were fewasymmetries in New World monkeys, with the exceptionof the protrusion of the left occipital region relative to theright (LeMay 1976).

With the advent of radiological techniques, it hasbecome clear that there are a number of asymmetries inthe brain. The first to be identified were ventricular asym-metries, shown by pneumoencephalography (PEG). Theleft lateral ventricle is usually (in ~ 70%) wider than theright, particularly anteriorly and in the tips of the temporalhorns (LeMay 1984). Earlier observations derived fromcasts of the ventricles made after death had shown the leftlateral ventricle to be larger in only 48 percent (Last andThompset 1953). However, for purely technical reasons itis likely that the higher value would be correct. Indeed, astudy of computed tomography (CT) scans of 100 normaladults again showed the left lateral ventricle to be widerthan the right in 62 percent, with the right wider in 32 per-cent. In addition, males showed a greater differencebetween the measurements on the two sides (Gyldensted1977).

Both the shape and the size of the lateral ventricles,particularly the occipital horns, show a correlation withthe shape and size of the brain and the skull (Bailey 1936;Berg and Lonnun 1966). When fetal brains were exam-ined at post mortem, it was found that the occipital hornsoccupied a much larger proportion of the overall ventricu-lar volume than they do later in life (Curran 1909). Itappears that as the brain increases in size, even after birth,the occipital horns become relatively smaller and moreasymmetrical. Ventricular asymmetries are quite clear bythe end of the first year of life (Lodin 1968), althoughthere are no data on whether there are gender differencesin the magnitude or timing of the development of thisasymmetry. In a PEG study of 100 right-handed adults,the left occipital horn was longer in 60 percent, and theright in 31 percent (McRae et al. 1968). When the same

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investigators examined a group of patients with epilepsy,they found a striking deviance from the normal pattern,with equal lengths in 60 percent of right-handers and 38percent of left-handers, suggesting an abnormality ofbrain development or possibly some other insult to thebrain. Similar findings were reported in young children.The left occipital horn was longer in 60 percent, but inthose who had developed epilepsy before the age of 1year, the two sides were either symmetrical or the rightwas longer (Strauss and Fitz 1980).

The association of structural and functional asymme-tries has received increasing attention. We have alreadyreferred to the typical Yakovlevian torque being moreaccentuated in right-handers and to the interactionsbetween handedness and the structure of the corpus callo-sum (Witelson 1989) and the Sylvian fissure (Witelsonand Kigar 1992). Frequently, however, there have beenlimitations in the analysis of handedness (Chapman andChapman 1987; Bryden and Steenhuis 1991), in the inter-pretation of structural data, or in controlling for gender orfor the presence of diseases that might affect the brain.Clearly, there are also individual differences in brainasymmetries and fiber composition in the corpus callo-sum, implying the need for large studies to segregate therelationships between handedness and callosal structure(Abbitiz et al. 1992). A CT study of children, 71 percentof whom had epilepsy, clearly demonstrated significantstructural asymmetries, but these did not correlate withmeasures of handedness (Deuel and Moran 1980).However, examination of the presented data reveals tech-nical difficulties in the interpretation of the scans, and aswe have already seen, epilepsy may be associated with adisturbance of the normal pattern of brain asymmetry.

In addition to these regional differences, there aremore generalized interhemispheric differences. The ratioof gray to white matter is smaller in the right hemisphere.The greater amounts of gray matter on the left are primar-ily in the motor, premotor, and primary sensory area (Guret al. 1980). These findings are consistent with the asser-tion that the left hemisphere is focally organized, whereasthe right is more diffusely organized (Semmes 1968).Data from a variety of sources indicate that hemisphericdifferences can be best understood in terms of specificprinciples that are relevant to defined cognitive functions.So the left hemisphere is superior at encoding visual cate-gories, but the right is better at representing overall visualpatterns (Brown and Kosslyn 1993).

Gender and Asymmetries of theNervous System

That there are hormonal influences on the brain is not in

doubt, A more challenging question is whether hormonesthemselves or the sex chromosomes may affect the struc-ture of the brain. In 1879, Crichton-Browne wrote that"the tendency to symmetry in the two halves of the cere-brum is stronger in women than in men" (p. 53). Althoughthere are wide variations, there does indeed seem to be atrue sexual dimorphism in the asymmetry of the brain(Bear et al. 1986). The hypothesis that prenatal exposureto testosterone could be responsible for differential rates ofbrain maturation and asymmetry has, as intended, gener-ated considerable interest and debate, although no firmconclusions (Geschwind and Galaburda 1984).

The gross structure of the brain appears to be thesame in males and females, with the exception of size dif-ferences, which appear themselves to be a function ofheight rather than gender (McGlone 1980; Janowsky1989). However, a number of lines of evidence indicategender differences in the maturation of the fetal andyoung child's brain. Furthermore, there is some evidenceof gender differences in a number of neuropsychologicaltasks ascribed to different hemispheres (for a review seeHalpern 1992). There is evidence in favor of these differ-ences being genetically determined. On tests of intelli-gence, patients with Turner's syndrome (XO) have per-formance deficits relative to verbal, which are consistentwith right hemisphere dysfunction (Netley and Rovet1982), and maldevelopment of heteromodal associationcortex in the right hemisphere (Christensen and Nielsen1981). By contrast, patients with an extra X chromo-some—Klinefelter's syndrome—and triple X syndromehave verbal deficits or delays, while their performance IQtends to be in the normal range, suggesting left hemi-sphere dysfunction (Netley 1986).

The most important conclusion from a number ofstudies has confirmed Crichton-Browne's observation thatthe male brain is indeed more symmetrical than thefemale. It has also become clear that the corpus callosumis larger in women, particularly in its more posterior parts(Witelson 1989; Kimura 1993), and that there are, in thecallosum, marked interactions between gender and hand-edness (Cowell et al. 1993). It has been suggested that alarger corpus callosum is associated with better interhemi-spheric transfer of information, which might contribute tothe statistically superior verbal fluency in women (Hines1990). This gender difference in the corpus callosum maybe relevant to the symptomatology of schizophrenia andthe different clinical expressions of the disease in men andwomen. There are structural abnormalities in the corpuscallosum in schizophrenia (Woodruff et al. 1993),although it is not yet known whether these abnormalitiesare modulated by gender. Several authors have found evi-dence of abnormalities in callosal transfer in schizophre-nia, but the precise nature of this remains the subject of

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considerable debate. Although there does appear to begood evidence of structural difference in male and femalebrains, particularly in more asymmetrical structures, thistheory has not found universal acceptance. For instanceJanowsky (1989) has argued that we do not know enoughabout the composition of neural networks to conclude thatthese structures are actually different in males andfemales.

One of the most contentious issues in neurobiology isthe reported association between sexual orientation andbrain structure. For instance, Allen and Gorski (1991,1992) have reported that the size of the anterior commis-sure varies with sexual preference. A further interestingreport showed an alteration of functional cerebral asym-metry during the menstrual cycle (Heister et al. 1989).Dopamine is lateralized, and it is also modulated by estro-gens; this may indicate a relationship between structure,neurochemistry, and hormones that could be relevant tothe differing clinical presentations of schizophrenia inmen and women. It may also be relevant that there arestructural and functional neuroendocrine asymmetries inthe brain (Wittling and Schweiger 1993), as well as aninterrelationship between cortical and autonomic asym-metries, both of which may have structural as well asphysiological bases (Gallhofer et al. 1993; Shannahoff-Khalsa 1993; Velikonja et al. 1993). These observationsmay be significant in view of the frequent observations ofdisturbances in autonomic, endocrine, and immunologicalfunction in schizophrenia.

An interaction between sex hormones and lateralitywas first suggested by Geschwind and Galaburda (1984;pp. 211-224). A later, refined version of this hypothesisposits that lower amounts of testosterone in the fetalfemale brain lead to less regression in the tempero-pari-etal region of the left hemisphere, with a consequentlylarger callosal isthmus. This, in turn, results in less func-tional asymmetry (Witelson 1991).

Crow (1993) has woven a number of different obser-vations into an ingenious hypothesis linking the differentages at onset of schizophrenia in males and females with,among other things, the gender differences in asymmetry.He has also correctly predicted that normal asymmetrywould be disturbed in schizophrenia. These concepts arevery important and will be discussed in greater detaillater.

Asymmetries of the CellularOrganization of the Brain

Many architectonic asymmetries have been identified inthe brain. While an examination of these lies outside ourimmediate field of interest, it is important to be aware that

the most consistent asymmetries have been identified inregions of heteromodal association cortex involved in lan-guage. For instance, von Economo and Horn (1930)showed that left-sided auditory association cortex, whichlies largely within the PT, is consistently larger on the leftside. A series of studies by Galaburda and his collabora-tors have confirmed and extended these findings(Galaburda et al. 1978, 1987, 1990; Galaburda andSanides 1980; Galaburda 1993). These asymmetries arenot confined to histology. In area Tpt, which occupies amajor portion of the PT and of the adjacent superior tem-poral gyms, there is a consistent increase in the amount ofcholine acetyltransferase on the left (Amaducci et al.1981). Further left-preponderant asymmetries have beenidentified in the inferior parietal lobule, another portion ofthe heteromodal association cortex with prominent lan-guage functions (Eidelberg and Galaburda 1984).

As might be anticipated, there is also an asymmetryof regions of the brain that enjoy close connections withthese language-specific regions. The posterior thalamusappears to be relevant to language functions (Bell 1968;Geschwind and Galaburda 1984; Ojemann 1991). It isusually the pulvinar that is implicated, but adjacent nucleiprobably also participate in language. One of these—thelateralis posterior nucleus of the thalamus—is larger onthe left, but only in individuals with a larger left PT(Eidelberg and Galaburda 1982). This nucleus does pro-ject to the inferior parietal lobule (Geschwind andGalaburda 1984). More recently a unique population oflarge neurons has been identified in the left hemisphere.These lie in layer III of the anterior language area(Brodmann's area 45), providing further support for astructural asymmetry in a region with marked functionallateralization (Hayes and Lewis 1993).

It is striking that the most marked asymmetries arefound in the PT and planum parietale (Jancke et al. 1994)and in parts of the dorsolateral prefrontal cortex. All ofthese lie within one of the most phylogenetically recentportions of the brain: a widely distributed but highly inter-connected system—the heteromodal association corticalregions of the cerebral cortex. These appear to providethe neurological substrate for higher functions of lan-guage, thinking, and ideation.

Structural Asymmetries Below the Tentorium. It hasbecome quite well recognized that asymmetries are foundat several levels of the nervous system. The decussationof the pyramids is asymmetrical in both fetal (Yakovlevand Rakic 1966) and adult human brains (Kertesz andGeschwind 1971). A further common asymmetry hasbeen described in the lower medulla: an aberrant circum-olivary bundle that may be involved in the innervation ofsome muscles of articulation (Smith 1904).

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Neurochemical Asymmetries. We have alreadyreferred to the asymmetry of choline acetyltransferaseactivity in the superior temporal gyrus (Amaducci et al.1981). In addition, the left pulvinar contains more norepi-nephrine than the right (Oke et al. 1978). Postmortemanalysis of neurotransmitters is notoriously difficult.Nevertheless, studies have indicated further left-rightasymmetries in the content of dopamine, glutamic aciddecarboxylase, and gamma aminobutyric acid in the basalganglia (Glick et al. 1982). Possible doubt about thevalidity of these findings has been allayed by discoveriesof similar biochemical asymmetries in the rat (Carlsonand Glick 1989). These asymmetries, particularly anincreased content of dopamine in the left globus pallidus,could have significant behavioral consequences. It hasbeen suggested that these asymmetries in rats may berelated to paw preference and hemionentation (Carlsonand Glick 1989). There are some data to suggest thatbehavioral lateralization of neonatal rats is related toasymmetries in cerebral dopamine (Afonso et al. 1993).In a more indirect, but potentially important study, chil-dren with early treated phenylketonuria, which is associ-ated with developmental dopamine depletion, were stud-ied on tasks of visual attention. The boys showed clearevidence of left-hemisphere dysfunction, but the girls didnot (Craft et al. 1992). If confirmed, this finding may wellhave far-reaching consequences for our understanding ofthe development of gender differences in functional, andperhaps also in structural lateralization. It is now clearthat dopamine turnover in the right and left nigrostriatalpathways is reciprocally regulated (Glowinowski et al.1984). A further famous and potentially behaviorally sig-nificant experiment involved the administration of lyser-gic acid diethylamide (LSD-25) to patients before andafter temporal lobectomy. It was shown that ablation ofthe right temporal lobe is associated with a disappearanceof the perceptual effects of the drug (Serafetinides 1965),implying an asymmetry of 5-hydroxytryptamine type 1Aand 2 receptors—the main site of action of LSD.

It is valuable to consider the interrelationships ofstructural and biochemical asymmetries. The latter appearto be a real phenomenon, not simply a reflection ofincreases or decreases in local tissue mass. However, theprecise interactions among structure, biochemistry, andfunction remain obscure. There are, however, some datato suggest that antipsychotic medications do have a lateral-ized effect. Acute treatment with haloperidol has lateral-ized effects on dopamine turnover in the rat brain (Jerussiand Taylor 1982). Furthermore, treatment is associatedwith a small but significant shift in electroencephalography(EEG) voltage to the left (Serafetinides 1973) and with lat-eralized alterations in visual evoked responses(Myslobodsky et al. 1983). This notion is buttressed by

the observation that unmedicated patients perform poorlyon tasks typically ascribed to the right hemisphere, such assorting shapes. However, treatment reverses the side ofthe deficit (Tomer and Flor-Henry 1989). These observa-tions are suggestive of an antipsychotic-induced inhibitionof function in the right hemisphere.

Schizophrenia

The possibility of a relationship between disturbances incerebral asymmetry and psychosis was first raised almost120 years ago (Crichton-Browne 1879). Other articles inthis issue of the Schizophrenia Bulletin deal with compo-nents of cerebral asymmetry. We shall not reiterate infor-mation in them, other than to point out that data derivedfrom several different types of studies have indicatedabnormalities in the left hemisphere. These studiesinclude neuropsychological testing (for a review seeNasrallah 1986); attention (Posner et al. 1988); auditoryacuity (Mathew et al. 1993); brain electrical activity map-ping (Morihisa et al. 1983); recordings of the P300 poten-tial (Morstyn et al. 1983; Holinger et al. 1992; Faux et al.1990, 1993); EEG (Morrison et al. 1991; Koukkou et al.1993); positron emission tomography (Gur et al. 1987;Berman and Weinberger 1990; Friston et al. 1992; Wilsonand Mathew 1993); single photon emission tomography(SPECT) (Suzuki et al. 1993); and biochemistry(Reynolds 1983; Kerwin et al. 1988). With so much evi-dence pointing toward the left hemisphere and/or animbalance between the two sides, it is not surprising that agreat deal of effort has been expended on the search forstructural asymmetries in schizophrenia. We must, how-ever, mention that although there is much to suggest lefthemisphere dysfunction in schizophrenia, some evidencesuggests that dysfunction in the right hemisphere, with adiminution of activity, is the key abnormality (Cutting1990, 1992, 1994; Persaud and Cutting 1991). Thesemodels, however, are not necessarily mutually exclusive.The normal state of affairs is a functional balance betweenand within each hemisphere: For virtually every task thereis a potential contribution from each hemisphere, althoughsome tasks tend to be preferentially mediated by onehemisphere or the other.

What has become known as the "typical" pattern ofanatomical asymmetry—a predominance of the left parieto-occipital regions—was described in the early years of thiscentury and was speculated to be related to the functionalspecialization of the hemispheres (Smith 1907). The possi-bility that mental disturbances might be related to somederangements of the normal pattern of asymmetry of thebrain had been raised by the detailed studies of Southard(1915) and subsequently by Inglessis (1925). However, in

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both cases, the findings were not conclusive and werelargely ignored during the years when psychological andsocial theories supplanted biological observations.

Southard's articles now appear prescient. Not onlydid he comment on ventricular enlargement (which hetermed "internal hydrocephalus"), but he stated quiteclearly that "the atrophies and aplasias when focal show atendency to occur in the left cerebral hemisphere"(p. 662). Finally, he also pointed out the predilection forthe pathological lesion to affect the "association centers ofFlechsig" (Flechsig 1908, 1920), which we would identifyas the interlinked system of heteromodal association cor-tex, which has recently been strongly implicated in thepathology of schizophrenia (Schlaepffer et al. 1994).More recently, interest in comparing the two hemisphereswas rekindled by the observations and subsequent theoriz-ing of differential behavioral effects of lesions in eachhemisphere, leading to a redistribution of the normal bal-ance between the two hemispheres (Flor-Henry 1969,1976, 1983). Flor-Henry reported that when psychosisdeveloped in association with an epileptic focus in the lefthemisphere, it tended to be schizophrenia-like, while afocus in the right hemisphere is more likely to be associ-ated with an affective psychosis. While initially theseobservations were thought to be relevant only to epilepsy,it was not long before a potential link to schizophreniaitself was being considered.

An early investigation using air encephalography hadreported ventricular enlargement restricted to the left sidein 9 of 27 chronic psychotic patients (Hunter et al. 1968).In two CT scan studies, it was reported that "density" ofthe left hemisphere was reduced on the left side inpatients but not in controls (Golden et al. 1981; Largen etal. 1983). This observation was subsequently replicatedin one study of chronic schizophrenia patients (Coffmanet al. 1984) and in another of monozygotic twins discor-dant for schizophrenia (Reveley et al. 1987).

Although the suggestion that asymmetry of the hemi-spheres may play some role in schizophrenia is normallyassumed to be a modern concept, the idea that distur-bances within the corpus callosum resulting in aberrantintrahemispheric communication might underlie psychoticillnesses was first proposed by Wigan in 1841 (Clarke1987). A development of the idea was proposed byJaynes (1977) in his well-known book, in which he pro-posed that many of the symptoms of schizophrenia couldbe ascribed to a relative overactivity in the right hemi-sphere of the brain, such that the experience of auditoryhaUucination actually represented the reception by the lefthemisphere of verbal activity by the right. Contemporaryobservation of reversal of the normal asymmetry of theplanum temporale may provide some support for this the-sis, if indeed this structure is active in the right hemi-

sphere. Over the years, a number of studies have exam-ined the function of the corpus callosum in schizophrenia,with interesting, but still inconclusive results (David1987, 1993; Doty 1989; Raine et al. 1989).

The most consistent in vivo finding in schizophreniais enlargement of the lateral ventricles, although a recentmeta-analysis has revealed that the degree of this enlarge-ment is much smaller than previously thought, and likesome other findings, the differences between normal con-trols and patients have tended to become smaller as morestudies have been performed (Van Horn and McManus1992). The finding, however, remains robust, and in somereports the enlargement has been found to be asymmetri-cal, the enlargement of the left being greater (Crow et al.1988, 19896; Crow 1990a; DeLisi et al. 1991, 1992).This preferential enlargement of the left lateral ventriclehas also been found in postmortem study (Brown et al.1986; Crow et al. 1989a). This investigation also con-vincingly demonstrated that this asymmetrical enlarge-ment was found only in patients with an antemortem diag-nosis of schizophrenia, but not in roughly matchedpatients with Alzheimer's disease, in whom the enlarge-ment was the same on the two sides. This enlargementeither reflects atrophy, or an arrest of brain growth, with aconsequent failure of the brain to attain the adult propor-tions of brain to ventricular volumes. One of the keyinquiries in research examining the neurobiological basisof schizophrenia is directed at establishing whether thesebrain abnormalities are progressive. It is also now emerg-ing that ventricular enlargement is most pronounced in thetemporal horns, again mainly on the left (Brown et al.1986), and is associated with schizophrenia symptoms(Degreef et al. 1992; Kawasaki et al. 1993). The presenceof enlarged ventricles has received such detailed examina-tion because it may be a marker of a particular subtype ofschizophrenia. Certainly, enlargement of the lateral ven-tricles is associated with an earlier age at onset (DeLisi etal. 1991, 1992). Enlargement of the third ventricle hasbeen associated with neuropsychological deficit(Bomstein et al. 1992).

In addition to the asymmetries in the ventricular sys-tem, temporal lobe size itself is reduced in patients withschizophrenia, again more on the left than the right(Bogerts et al. 1990; Dauphinais et al. 1990). In two post-mortem studies, the normal asymmetry of the lateral(Sylvian) fissure (left longer and flatter than the right) wasfound to be lost in schizophrenia (Crow et al. 1992; Falkaiet al. 1992). However, it remains uncertain whether thereduction in temporal lobe volume is already present atthe time of the onset of the illness (DeLisi et al. 1991,1992). There has also been debate about whether bothgray and white matter are decreased (Suddath et al. 1989;Zipursky et al. 1992) or whether the reduced volume is

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localized to only some regions of the temporal lobe, suchas the superior temporal gyros (Barta et al. 1990; Shentonet al. 1992); the PT (Hoff et al. 1992; Rossi et al. 1992;Bilder et al. 1993; Petty et al. 1995); or the medial parts ofthe temporal lobe, specifically the hippocampus andamygdala (Delisi et al. 1986; Bogerts et al. 1990). Theleft hippocampus is usually reduced in volume in patientscompared with controls (Breier et al. 1992). The leftparahippocampal region has been found to have a reducedvolume compared with matched controls (Young et al.1991; Kawasaki et al. 1993). More recently, DeLisi et al.(1994) examined the temporal lobes of a large group ofpatients with schizophrenia and demonstrated a reductionin the normal pattern of asymmetry in more anterior partsof the temporal lobes and, in females only, a trend towardless asymmetry posteriorly. They were unable to findreductions in the volume of the anterior portions of theleft temporal lobe. However, as the authors themselvesacknowledge, there were technical limitations in thisstudy: 5 mm slices were used with 2 mm gaps—far largerthan those used in studies reporting positive findings.

As work on brain structure in schizophrenia has pro-gressed, further efforts have been made to relate devia-tions of symmetry to specific clinical features. Hoff et al.(1992) found anomalous asymmetry of the Sylvian fis-sure, particularly in women. Interestingly, it was nega-tively associated with cognitive dysfunction. This is sur-prising, given the prevailing view that cognitivedysfunction is more likely to be associated with aberrantneurodevelopment (Buckley et al. 1993; Buckley andO'Donovan 1994). In another study, increased volume ofthe Sylvian fissure was found, but only in male schizo-phrenia patients (Ron et al. 1992). Finally, two studieshave found clear associations between alterations in thenormal asymmetry of the PT and thought disorder (Rossietal. 1994; Petty etal. 1995).

We are obviously still at an early stage of the investi-gation of structural asymmetries. While we have men-tioned several studies in which clear asymmetries havebeen identified, others have failed to make the sameobservations. It is important to point out these negativereports. For instance, Bartley et al. (1993) and Kulynychet al. (1993) performed careful studies of 10 patients withschizophrenia who had unaffected monozygotic twins and10 with dizygotic twins; they were unable to detect differ-ences in normal asymmetries in the schizophrenia-affected twins. Similarly, Kleinschmidt et al. (1994) wereunable to demonstrate a deviance of normal asymmetry infirst-episode schizophrenia patients. Other studiesdirected toward different cortical and subcortical struc-tures have failed to detect consistent asymmetries(Casanova et al. 1990; Jernigan et al. 1991; Degreef et al.1992; Levy et al. 1992). There are a number of reasons

for these different results. The most important reflect thepopulations selected: Most have studied chronic malepatients, and, as we have seen, there are good reasons forexamining males and females separately. Furthermorethere continue to be different technologies in use. It alsohas proven difficult to directly compare MRI analysis pro-grams developed in different centers.

There are two major reasons for the concentration onthe temporal lobes in schizophrenia. One is the associa-tion between temporal lobe epilepsy and schizophrenia-like psychoses. The second is the association betweenschizophrenia and disorders of language (Andreasen1979a, 1979ft), because the many regions of the braininvolved in the reception and production of language liein the superior portions of the temporal lobe.

Reduced asymmetries of the length of the PT havebeen reported in individuals with developmental dyslexia(Geschwind and Galaburda 1984; Larsen et al. 1990).Several studies have shown clear disturbances of the nor-mal asymmetry of the planum temporale in patients withschizophrenia. Two were postmortem studies (Crow et al.1992; Falkai et al. 1992), and five were in vivo (Hoff et al.1992; Rossi et al. 1992; DeLisi et al. 1994; Kleinschmidtet al. 1994; Petty et al. 1995). All but the DeLisi groupstudy showed reduction in the normal asymmetry of thearea, and the degree of reduction appears to be related tothe resolution of the methodology employed. Petty andcolleagues used perhaps the highest resolution SPGRscans yet employed in studies of the region and found notjust a loss of normal asymmetry but a complete reversal,in a small study of 14 patients. However, the power ofthis study was amplified by the use of extremely rigorousmatching of controls to patients.

In 1979, Luchins et al. reported reversal of the nor-mal asymmetries of the occipital and frontal lobes insome patients with schizophrenia; that is, the patients hadwider right occipital lobes than left, and their left frontallobes were smaller than the right. Subsequently, Naeser etal. (1981) and Tsai et al. (1983) reported reversals ofasymmetry in the occipital but not the frontal lobe, andLuchins et al. (1981) replicated their earlier finding ofreversal of occipital lobe asymmetry. However, the situa-tion became much less clear as a number of negativereports began to appear (Andreasen et al. 1982; Jemiganet al. 1982; Nyback et al. 1982; Weinberger et al. 1982;Luchins and Meltzer 1983). In a critical review, Luchins(1982) himself concluded that the only significant andconsistent finding was larger right frontal and left occipi-tal brain regions in normal as well as affected individuals.An analysis of all the studies published up until 1983demonstrated the familiar observation that in biologicalmeasurement the size of the effect tends to diminish as afunction of the level of experimental control.

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During the 1980s, Timothy Crow developed an inge-nious hypothesis Unking the neurological lesions of schiz-ophrenia to the development of cerebral asymmetry, andhe and his collaborators embarked on a number of investi-gations to test this hypothesis. At its simplest, the hypoth-esis proposes that schizophrenia is a disorder of thegenetic mechanisms that control the development of cere-bral asymmetry. The prediction from this theory is thatthe greatest disturbances will be seen in regions that nor-mally show the highest degrees of asymmetry, such as theplanum temporale. This prediction has subsequently beenborne out. Furthermore, as additional studies have beenperformed, more data have supported the contention thatthe normal torque to which we referred earlier is dimin-ished or absent in schizophrenia (Falkai et al. 1992). Thisloss of torque can be detected in groups with an earlyonset (Crow et al. 1989b) and in individuals experiencinga first episode (Bilder et al. 1993, 1994). An alternativeexplanation for the association between left-hemispherelesions and schizophrenia relates to the differential matu-ration of the right and left hemispheres, which renders theleft hemisphere more vulnerable to potential insults in thesecond trimester of pregnancy. Thus it would follow thatstructural asymmetries are an artifact of the timing of theinsult (Bracha 1991).

CT and MRI studies have shown remarkable agree-ment with results obtained from postmortem studies.Most authors, as we have seen, have reported that the PTis larger on the left and that the Sylvian fissure extendsfarther back on the left and rises more steeply on the rightHowever, the volume of the temporal lobe is on averagelarger on the right (LeMay 1986). In a group of 25healthy individuals, Jack et al. (1988) found temporal lobevolumes to be an average of 15.7 percent greater on theright side. However, a considerable range in the valueswas reported with no attempt to examine the potentialeffects of gender or handedness. Studies that havereported temporal lobe volumes in patients with schizo-phrenia have found that this right-greater-than-left asym-metry is maintained, although the degree is reduced.Thus, Suddath et al. (1989) found right temporal lobe vol-umes 15.5 percent greater than the left in controls, butonly 12.5 percent greater in patients. In a further studythe increased volume of the right was 13.6 percent in con-trols and 8.6 percent in patients (Harvey et al. 1993).

Although some MRI studies have not shown a signif-icant asymmetry of temporal lobe volume in schizophre-nia patients or controls (Shenton et al. 1992), a reversal ofthe normal pattern of asymmetry (i.e., left larger thanright) has been reported in some patients with schizophre-nia (Luchins and Meltzer 1983; Tsai et al. 1983). In alarge study of patients with late paraphrenia (late-onset

psychosis), Howard et al. (1994) found temporal lobe vol-ume to be greater on the right in elderly controls (2.6%),in schizophrenia patients (5.9%), and in patients withdelusional disorder (8.4%). This asymmetry was signifi-cant in both the schizophrenia and delusional disorderpatients, but not in the controls. These results appear tobe the reverse of the situation reported in young peoplewith schizophrenia. The explanation is not readily appar-ent, particularly because there are so few normative datapertaining to brain volume measurements in the elderly.It may be, as the Howard group speculates, that normalaging is associated with a gradual loss of the asymmetryof brain volumes seen in younger adult life. Persistenceof this asymmetry could then be a risk factor for the even-tual development of schizophrenia or delusional symp-toms. Considerable data collected in a variety of studiesindicate that there is normally a balance between theactivity of the two hemispheres, and convincing argu-ments have been advanced to suggest that schizophreniasymptoms may be linked to a predominance of righthemispheric activity (Cutting 1990) or left hemisphericunderactivity (Gur 1979). The Howard group previouslyfound an asymmetrical dilatation of the lateral ventricles,with significantly greater dilatation on the left, in patientswith both delusional disorder and late-onset schizophre-nia, compared with controls (Howard et al. 1994). Thispresumably reflects either arrested development of the lefttemporal lobe or, alternatively, increased loss of tissue onthis side of the brain. Whichever explanation proves to becorrect, this finding is consistent with that reported byCrow et al. (1988, 1990a, 1990*).

The precise delineation of the frontal lobes presents anumber of technical difficulties that have hinderedprogress in this area. However, as we discussed earlier, atpostmortem the total volume of the right frontal lobe isabout 13 percent larger than the left (Weinberger et al.1982). The direction and approximate magnitude of thisasymmetry have been confirmed using CT in normal indi-viduals (LeMay and Kido 1978; Chui arid Darnasio 1980).In MRI studies, there does not seem to be a significantdifference in the relative sizes of right and left prefrontalregions when controls and schizophrenia patients arecompared: Both show right side enlargement (Suddath etal. 1989). However, the situation appears to be differentin the elderly. The volume of the right frontal lobeexceeds the left by 1.7 percent in controls, by 0.3 percentin patients with late-onset schizophrenia, but by 8.5 per-cent in patients with delusional disorder (Howard et al.1994). It may be of interest that Swayze et al. (1992),while still finding the right temporal lobe to be larger thanthe left in schizophrenia patients, found small reductioncompared with controls but also found that right and lefttemporal lobes were of equal volume in females with

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bipolar disorder, once again demonstrating the importanceof gender as an independent variable.

The comparison of early- and late-onset schizophre-nia may present a useful avenue for further exploration, asmore sophisticated attempts are made to relate symptomsto the neurobiological substrates of these illnesses.However, such a comparison is not without its problems.With increasing age there appears to be a progressiveincrease in interindividual differences in brain appearance(Jacoby et al. 1980). Therefore, the demonstration ofminor structural abnormalities in the brains of older psy-chiatric patients becomes difficult, when compared withage-matched elderly controls. Thus, some of the subtleMRI findings reported in early-onset schizophreniapatients may be difficult to detect in the elderly, and theconsistent findings in the temporal lobes, particularly inelderly patients with delusional disorder, are thereforelikely to be robust

One of the more interesting approaches to the studyof the organic substrate in schizophrenia is the attempt toassociate structural and functional abnormalities. Therehave been several recent attempts to do this. In a study of31 schizophrenia patients and 33 volunteer controls, audi-tory P300 event-related potential and smooth pursuit eyemovement abnormalities were associated with structuralbrain changes measured using MRI. In the schizophreniagroup, P300 latency correlated negatively with the area ofthe right and left cingulate cortex and positively with thedifference in size of the right and left amygdala. Theresults were more marked in the more severely affectedindividuals. In those schizophrenia patients whose P300latency was greater than two standard deviations abovethe control mean, the area of the left cingulate cortex wassignificantly smaller than in controls, and the absoluteright-left difference in the area of the amygdala was sig-nificantly increased. Eye-tracking dysfunction in schizo-phrenia was not related to changes in the amygdala or cin-gulate cortex, but it was significantly correlated withenlargement of the lateral ventricles. There was no spe-cific association with enlargement of one side or the other.Schizophrenia subjects with poor eye-tracking had signifi-cantly larger lateral ventricles than controls. Eye-trackingdysfunction, but not P300 abnormality, was correlatedwith the severity of both positive and negative symptomsof schizophrenia (Blackwood et al. 1991). McCarley etal. (1991, 1993) have identified a clear associationbetween reductions of the volume of the left posteriortemporal gyrus and abnormalities of the auditory P300potential. Because this is the same region of the brainassociated with thought disorder (Shenton et al. 1992;Rossi et al. 1994; Petty et al. 1995), the obvious implica-tion is that this lateralized neurophysiological measure isproviding information about the substrate of disturbances

in communication. What these data appear to be telling usis that more severe deviations of normal cerebral asym-metry are associated with more marked disturbances inone particular measure of neurological dysfunction inschizophrenia- This may be of importance in view of thedata suggesting an association of handedness with tardivedyskinesia (McCreadie et al. 1982; Barr et al. 1989;Joseph 1990), even though handedness is, as we have dis-cussed, a poor indicator of structural asymmetry.

We have referred to possible dynamic changes infunctional laterality during the menstrual cycle. In oneinteresting study, sadly not replicated, a dichotic listeningtask showed a close relationship between disturbance oflaterality and psychotic symptoms: When the patient wasmost ill, laterality was most disturbed, and recovery wasassociated with a return to near normal laterality (Wexlerand Heninger 1979). It is tempting to speculate that thebetter prognosis of females with schizophrenia is associ-ated with the female brain being more plastic in contrast tothe greater structural asymmetries found in males, whichhave the effect of forcing a functional lateralization.

In our view, structural and functional asymmetries,and particularly their integration with clinical measures,still have much to teach us about schizophrenia.

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Acknowledgments

We gratefully acknowledge the assistance of the librarystaff at the Institute of Psychiatry, London: the Library ofthe Royal Society of Medicine, London; and the Van Peltand Biomedical Libraries, University of Pennsylvania.

The Author

Richard G. Petty, M.D., is Assistant Professor, Universityof Pennsylvania, Department of Psychiatry, Philadelphia,PA.

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