10.1192/bjp.170.4.328Access the most recent version at doi: 1997 170: 328-333 The British Journal of Psychiatry

  S Frangou, T Sharma, T Sigmudsson, P Barta, G Pearlson and RM Murray  

asymmetry in familial schizophrenia. A volumetric MRI studyThe Maudsley Family Study. 4. Normal planum temporale  

References

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measurements from 3-D reconstructedmagnetic resonance imaging (MM) scans,in schizophrenic patients and their unaffected first-degree relatives from familiesmultiply affected with schizophrenia.

METHOD

Subjects

Thirty-two schizophrenic patients (21 men,11 women) and 55 of their non-schizophrenic first-degree relatives (24 men, 31women) from 16 families multiply affectedwith schizophrenia, agreed to participatein this study. Families were classified asmultiply affected if two or more memberssuffered from schizophrenia. The familieswere recruited nationwide by referralsfrom regional services and voluntaryorganisations.

Allschizophrenic patients met DSM—ffl—R(American Psychiatric Association, 1987)criteria for schizophrenia. They lived inthe community and all but one receivedregular antipsychotic medication. Of the55 relatives, 47 had no personal history ofmental illness, while eight had a history ofaffective disorder. None of these relativeswas acutely ill at the time of testing.

Patients and their relatives were compared with 39 normal controls (19 men, 20women) recruited from the local community. None of the controls had any personal

or family history (up to second-degreerelatives) of psychosis. Exclusion criteriafor the entire sample included head traumaresulting in loss of consciousness, drug andalcohol misuse, and hereditary neurologicaldisorders. All subjects were informedabout the purpose and the proceduresinvolved in the study and gave writtenconsent.

Clinical assessments

Schizophrenic patients, their relatives andthe normal controls were assessed bypersonal interview by one of the authors(T. Sigmudsson) who was blind to diagnosisand family status. Research DiagnosticCriteria (RDC; Spitzer et a!, 1978) andDSM—III—Rdiagnoses were made using theSchedule for Affective Disorders andSchizophrenia —¿�Lifetime Version (Endicott& Spitzer, 1978). Family history wasobtained from all subjects based on theFamily History Research DiagnosticCriteria (Endicott et a!, 1975). Socioeconomic status was determined according tothe standard occupational classificationpublished by the Office of Population

Background Lossor reversalofthe

normal asymmetry ofthe planum

temporale (PT) has been reported in

schizophrenia, and may be due to

aberrations in the gene(s) controlling the

development of brain asymmetries.We

tested this hypothesisin asampleof schizo

phrenics and their relatives from families

multiply affected with the disorder.

Method We compared32schizo

phrenics and 55 oftheir non-schizophrenic

first-degree relatives with 39 matched

Community Controls.Volumetric measure

mentsofthe cortical volume beneaththe

PTwereobtained usingthe Cavalieri

method from three-dimensionallyre

constructed magnetic resonance imaging

images.

Results PTvolumeasymmetrycoefficients from patients and their relatives did

not differ significantly from those of the

controls.Gender-specific analysis did not

reveal any differences.

Conclusions AbnormalitiesinPTvolume asymmetry are not present in

familialschizophrenia,where genetic

factors appear to predominate.

Normal brain development leads to anatomical asymmetries which are establishedin utero and are under strong genetic control(Geschwind & Galaburda, 1985).According to Crow (1990), anomalies inlanguage organisation in schizophrenia maybe consequenton a defect in the gene(s)controlling normal development of temporallobe asymmetries. In accordance with thisproposition, research interest in schizophrenia has focused on the planumtemporale (PT). The PT is a triangularplane that lies on the superior temporalgyrus and forms part of the biologicalsubstrate for language. Its surface area ishighly asymmetrical and in nearly 65% ofthe normal population it is larger on the leftthan on the right (Geschwind & Galaburda,1985). The degree of P'F asymmetry is

modulated by gender and handedness,being reduced in women and left-handedindividuals (Geschwind & Galaburda,1985).

Although the pattern of asymmetries inthe PT surface area is well documented, littleis known regarding the volume of the cortexlying beneath the PT. A post-mortem studyby Falkai et a! (1995) suggests that this alsoshows leftward asymmetry, but the relationship between PT volume and area has notbeen systematically explored (Barta et a!,1995).

Findings of studies of PT asymmetry inschizophrenia, summarised in Table 1, havebeen contradictory. Methodological issuespartly account for this, since confoundingfactors such as gender or handedness areoften not considered, and the definition ofthe PT borders varies greatly. Most importantly, none of the previous studies has fullyexplored the possibility of a genetic linkbetween schizophrenia and abnormal PTasymmetry. If such a link exists thenabnormal PT asymmetry should be particularly prevalent in cases in which geneticfactors appear to predominate.

In order to address this question, weexamined PT asymmetry, using volume

328

The Maudsley Family Study 4. Normal planum

temporale asymmetry in familial schizophrenia

A volumetric MRIstudy

S. FRANGOU, T. SHARMA, T. SIGMUDSSON, P. BARTA, G. PEARLSON

and R. M. MURRAY

Study Sample Methods Findings Comments

Table I Studiesofsylvianfissure(SF)andplanumtemporale(PT) asymmetryinschizophrenia

Falkaieta! 35schizophrenicbrains,33

(I 992) non-psychiatric control

brains

52 first-episode schizophreni

form patients, 30 normal

controls

Rossi et a! 20 right-handed schizo

(l992) phrenics,2 right-handedcontrols

Kleinschmidt 26 first-episode right-handed

et a! ( I994) schizophrenics. 26 right

handed normal controls

Dc Lisi et a! 85 first-episode patients with

(1994) schizophrenia, schizo

affective and schizophreni

form disorder, 40 normal

controls

Falkaieta! 24schizophrenicbrains,

(1995) 24 non-psychiatric control

brains

Petty et a! 4 right-handed schizo

(1995) phrenics, 14right-handed

controls

Kulynycheta! I2 right-handedschizo(1995) phrenics, 12right-handed

controls

Post-mortem study; SFlength

measured on photographs of

brains; the ascending ramus

wasnotincluded

Serial sagittal 5 mm non

contiguousMRIslices;two

measures SFlength, one

including and one excluding

the ascending ramus

Serial coronal 3 mm non

contiguous MRI slices; PTarea

measurements acquired by

multiplying lengthofSFby

slicethickness

SagittalI.5 mmcontiguousMRI

segments ofthe SFmeasured

separately; total SFlength

included the ascending ramus

Serial sagittal I .7 mm contiguous

MRI slices; PTarea measurements

obtained by multiplying curved length

measurements with slice thickness; the

posterior border ofthe PTexcluded the

ascending ramus

Serial coronal 5 mm non-contiguous MRI

ReducedSFasymmetryinpatients; trend for this

reduction to be more

pronounced in male

patients

No overall group differences

in SFasymmetry; female

patients showed reduced

lateralisation in the extended

SFmeasurementReduced PTarea asymmetry Definition ofthe posterior

in patients. with a non- border ofthe SFunclear;

significant trend for PTarea possibly including the

to be reduced on the left and ascending ramus; gender

increased on the right taken into account in data

analysis

No difference in SFasymmetry Effects oftwinning on brain

betweenaffectedand asymmetriesunknownunaffected twins or between

normal and discordant twin

No group difference in PTarea Definition of Plused had been

asymmetry; no effect of validated in human cadaver

positive family history of brains

schizophrenia on PT

asymmetry

ReversalofPTsurfacearea Closedemographicmatchingasymmetry in patients found betweencontrolsand patients

using both measurement

methods

Genderbutnothandednessaccounted for in data analysis;

SFmeasured indirectly from

photographs

Hoffet a!

(1992)No difference in handedness

betweenpatientsandcontrols

Bartley et a! 0 monozygotic twins

(1993) discordant for schizophrenia, slices from which 3-D renderings

I0 normal monozygotic twins were obtained; different

pairs

No group differences in PT Measurements limited to six

slicesslices;PTareameasurementsacquiredby areaasymmetry;female

multiplying lengthofSFbyslicethickness; patientsshowedreduced

laterality wasalsoassessedfor eachslice laterality inonesliceonly

Post-mortem study; coronal 20 @im

contiguous slices; PTarea measurements

obtained by planimetry from magnified

paper drawings; volume ofthe cortex

underlying the PTand SFlength were also

calculated

Coronal I .5 mm contiguous MRI slices; PT

area measurements acquired by multi

plying length ofSF by slice thickness and

by tessellation ofPTsurface area in 3-D

reconstruction

SagittalI.5 mmcontiguousMRIslicesfrom No group differencesin PT Thesurfaceareaofthe Heschl'swhich 3-D renderings were obtained; PT area asymmetry gyrus was also measured and

area measured by surface rendering showed no asymmetry in

morphometry; the ascending ramus in either group

ofthe SFwas excluded from PT

measurements

Reduced SFand PTvolume

asymmetryin patients;no

overall group differences in

PTarea asymmetry

Effectsofbrainshrinkagecannot be excluded;

subjects'handednessnotknown

329

Censuses and Surveys (1991). Retired orunemployed relatives and normal controlswere classified according to their lastoccupation. Schizophrenic patients wereclassified according to their paternaloccupation. Handedness was determinedby the Annen handedness scale (Annett,1970).

MRI acquisition parameters

MM data were obtained using a GE Signa1.S-T scanner. A set of 1.5 mm thickcontiguous coronal MM images extendingthrough the entire brain were obtainedusing a 3-D spoiled gradient recall echosequence (time to echo S ms, repetitiontime 35 ms, one excitation, field of view20 cm, acquisition matrix 256 x 256 andFlip angle 350)

MRI image analysis

These images were used to produce a 3-Dvolume-rendered reconstruction of the brainusing MEASURE(Barta et a!, 1997a, in press),a program developed at the Division ofPsychiatric Neuroimaging at Johns HopkinsUniversity. This system runs on PCs underthe Windows operating system and has beenvalidated by studies using phantoms.MEASURE allows the user to view the image

voxels in three mutually orthogonal planesand places a 3-D grid of small rotated Lshaped points over the entire image. Adjacent grid points occur at the apices of theelementary cuboid, which is a generalisedcube with unequal length edges. The initialplacement of the grid on the volume israndom, which is essential for generatingunbiased volume estimates (Gundersen &Jensen, 1987). Using a mouse, the ratermarks all the grid points falling within thestructure of interest in all three views. Pointsmarked in one plane are automaticallymarked in the other two. Grid points onthe boundary of the structure are marked aswithin the structure only if the pixel withinthe acute angle of the L is inside thestructure, ensuring that voxels on theboundaries of structures are counted properly (Gundersen et a!, 1988). After all thegrid points within the region of interest aremarked, the program counts the totalnumber of marked grid points and convertsthis number to a volume by multiplying it bythe volume of an elementary cuboid. Thesize of the grid (i.e. the space between thepoints) can be adjusted, depending on thesize of the structure to be measured. Beforebeginning a study, the optimal grid size must

be determined through trial and error.Volumes are obtained using different gridsizes, until the largest grid is determined thatyields estimated coefficients of error of lessthan 5% for volume estimates from anyplane, using both Gundersen's formula(Gundersen & Jensen, 1987) and a refinement version (Pache et a!, 1993). In general,we found that a minimum of 200 points perstructure are needed.

Initially, the brains studied were manually stripped of skull, dura matter andsubdural cerebrospinal fluid (CSF) bytracing around the outer surface of thebrain. We then calculated the size of thegrid that would yield 200 points in thesmallest of the structures being measured,and applied the same grid to all structures.The grid used measured 4.5 x 4.5 x 1.5 mmwith the smaller dimension in the coronalplane. Window settings (e.g. magnification,contrast, brightness) remained constantthroughout the study. Measurement fileswere then saved and exported to EXCELviadirect data export. The volume of thestructures was calculated by EXCELusing amacro function.

Volume measurements

All ratings were done by the same investigator (S. F.) after the entire sample had beencollected. Scans were mixed and identifiedby number only so that the investigator wasblind to diagnosis and family status. Headtilt was corrected in all brains prior to anymeasurements by aligning the brain alongthe anterior—posterior commisure line in thesagittal plane, and along the intrahemispheric fissure in the coronal and axial planes.The following volumes were measured:

(a) Whole brain. This included cortical andsubcortical grey matter, white matter,the cerebellum, ventricular CSF and thebrain stem superior to the foramenmagnum.

(b) Superior temporal gyms (STG). TheSTG was measured in the rostrocaudaldirection from the first coronal slicewhere the temporal stem was visibleuntil the point of upward angulation ofthe posterior ascending ramus of thesylvian fissure, which was more easilydiscernible in the reconstructed parasagittal sections. The superior temporalsulcus was used as the inferolateralborder and the circular sulcus as themedial border.

(c) Heschl's gyms (HG). HG was identifiedby its retroinsular origin with the

transverse sulcus serving as its posteriorborder (Steinmetz et a!, 1989). Whentwo HG were present, the posterior onewas included in the PT (Steinmetz et a!,1989).

(d) Planum temporale (PT). In order todefine the borders of the PT we followedthe criteria used by Steinmetz et a!(1990) which have been validated inhuman cadaver brains. The transversesulcus, recognised by its retroinsularorigin, was used as the anterior borderof the PT. The posterior border wasdefined as the point of the upwardangulation of the posterior ascendingramus of the sylvian fissure, and thelateral border as the lateral border of thesupratemporal plane. The 3-D view ofthe PT afforded by MEASUREwasparticularly helpful in identifying ambiguous areas, especially the anterior andposterior borders. The reconstructedaxial slices allowed for the identificationof HG, especially in cases wheresecondary transverse sulci could be seen.

(e) Volume asymmetry coefficients. Anasymmetry coefficient for the PT wascalculated from the following equation[(left PT volume —¿�right PT volume)/0.S(right PT volume + left PTvolume)]. Anasymmetry coefficient for HG was alsocalculated in the same way.

Intra-class correlation coefficients forintra-rater reliability were over 0.91 for allmeasurements. The interrater coefficientbetween two raters was based on arandom sample of 10 brains and was over0.92 for all the volumes measured.

Statistical analysis

One-way analysis of variance was used tocompare the three groups on age, and ftests to compare the distribution of socioeconomic status, handedness and genderamong the three groups. One-way analysisof variance with age and gender as covariateswas used to compare whole brain volumes inthe three groups. To compare the volumes ofthe STG (leftand right), PT (leftand right) andHG (left and right) in the three groups,multivariate analysis of variance was usedwith diagnosis, handedness and gender bygroup interaction as main effects, and ageand whole brain volume as covariates.Analysis of variance with diagnosis,gender and handedness as factors was alsoused to compare asymmetry indices for thePT and HG.

330

Schizophrenics (ri

Mean (s.d.)=32)

Relatives (n=55) Controls (n=39)

Mean (s.d.) Mean(s.d.)Age(years)

37.5 (12.3)46.3 (14.6) 33.4(12.0)Gender(%male)65.643.651.2Handedness

(% left) 9.37.210.2Socialclass(%socialclassl)

15.618.12.5Education

(years) 12.4 (2.3)2.5 (3.2) 13.0(5.0)Age

ofonset ofsymptoms (years) 20.2(3.2)Duration

of illness (years) 14.9 ( I0.8)RESULTSThe

asymmetry coefficients for the PT andHG did not differbetweenthe three groups(F2=0.13, P=0.87 and F2=0.81, P=0.44,

respectively).Characteristics

of subjects

The clinical and demographic characteristicsof the subjects are shown in Table 2.Therelatives

were significantly older than theother two groups (F2=11.75; P=0.001),while there was no significant age differenceDISCUSSIONPredictionsandfindingsbetween

controls and schizophrenics. Socio We measured the volume of the STGandeconomicstatus (parental social class) wasHG and of the cortex underlying theplanumevenly

distributed in the schizophrenic andtemporale in a group of familial schizocontrol group, with the exception of asignificant relative excess of schizophrenicsfrom social class 1 (Pearson's @2=17.82,phrenics,

their non-schizophrenic relativesand unrelated normal controls. No significant differences were detected in any ofthed.f.=8,

P=0.022).above measures. Normal subjects showedaGenderdistribution (Pearson's @2=3•9@7,left@ard asymmetry in PTvolume,d.f.=2,

P=0.138) and handedness (left, rightand mixed) (Pearson's @=0.24S, d.f.=2,suggesting

a similar direction of lateralityas that reported for PT surfaceareaP=0.884)

were similar in all three groups.measurements. The degree of PT volumeasymmetry in normals was much lessthanMRI

measurementsthatreported for PT surface area (Table 1).

In this respectour findingsareconsistentThemean volumes ofthe structures measuredwith those of Falkai et a! (1995) in theonlyaresummarised in Table 3. There was noother published study to examinethesignificant

effect of group (app. F52=1.26;cortical volume of thePT.Wilk'slambda=zO.28), handedness (F6=0.8;Our hypothesis that there wouldbeWilk'slambda=0.SS), or group by genderchanges in the cortical volume of thePTinteraction

(app. F12=1.14; Wilk's lambda=(assuming it is proportional to surface areaif0.32)in any of the volumetric measurements.cortical thickness remains constant)inTable

3 Meanvolumetricmeasurements(s.d.)Volume

ofregion (cm3) SchizophrenicsRelatives (rs=55) Controls(n=39)(n=32)Whoiebrain

i 178.1 (133)I 174.7 (124) I 192.7(130.5)Leftsuperiortemporalgyrus

14.9 (2.9)15.4 (3.4) 4.6(1.9)Rightsuperiortemporalgyrus

4.0 (2.1)5.0 (2.9) 4.6(2.1)Leftplanumtemporale

5.9 (2.2)6.2 (2.0) 6.1(l.4)Rightplanumtemporale

4.7 (1.9)4.9 (1.7) 5.2(1.8)LeftHeschl'sgyrus

5.5 (1.6)5.7 (2.4) 4.9(1.3)RightHeschl'sgyrus

5.9 (1.6)6.2 (1.7) 5.7(1.8)PTasymmetrycoefficient'

0.11 (0.3)0.11 (0.2) 0.10 (0.2)

familial schizophrenia was not upheld.Schizophrenic patients and their relativesalso showed leftward asymmetry of PTvolume and no significant difference in the

direction of laterality was detected in thethree groups. This differs from the findingsof Falkai et a! (1995) who showed that thedirection of asymmetry of the volume of thePT was reversed in schizophrenics. However,they also included the cortex underlying theascending ramus of the SF in their measurement of the PT volume. It is likely that thisdefinition confounds the issue of PT volumeasymmetry as it combines the measurementsof two areas that in normal brains show areverse pattern of asymmetry; the PT shows

a leftward asymmetry while the cortical areaon the posterior ramus of the SF showssignificant rightward asymmetry (Steinmetzet a!, 1990). In addition, no handedness datawere available for either patients or controlsand, as the authors acknowledged, theeffects of brain shrinkage following fixationcould not be accurately estimated.

Relationship between PTvolumeand area measurements

Since we measured the PT cortical volume,our results regarding PT lateralisation arenot directly comparable with previousreports which used PT surface area measurements. The relationship between area andvolume measurements is complex. Barta eta! (1997b, in press) addressed this issue bymeasuring both the volume and surface areaof the PT in MM brain scans of schizophrenics and controls. The right PT area intheir sample of schizophrenics was largerthan the left, resulting in reversal of PTsurface area asymmetry. However, in agreement with the findingsin this study, the PTvolume measurements showed the normalleftward asymmetry and were similar tothose of controls. The reason for thisdiscrepancy appeared to be a 50% reductionin the cortical thickness of the right PT inthe patients.

To the extent that comparisons can bemade, our findings are similar to those ofother studies that have attempted to addressthe genetic relationship between schizophrenia and PT abnormalities. In a recentMM study on PT surface area asymmetriesin first-episode schizophrenics, Kleinschmidtet a! (1994) did not find any difference in PTlateralisation between schizophrenics andcontrols, nor any effect of positive familyhistory of schizophrenia on PT asymmetrycoefficients. Similarly, an examination of PT

Table2 Characteristicsofsubjects

331

surface area asymmetries in monozygotictwins discordant for schizophrenia revealednormal PT asymmetry in the schizophrenictwins (Bartley et a!, 1993).

As previously mentioned, PT asymmetryis correlated with handedness. Familialsinistrality accounts for most of the anatomical difference between right and lefthanders, thus emphasising the geneticcontribution to the development of PTlateralisation (Steinmetz et al, 1991). Theabsence of increased prevalence of anomalous handedness in the schizophrenicpatients and their relatives also supportsthe finding of normal PT lateralisation inour sample.

The possibility of changes in PT surfacearea asymmetries in our sample of schizophrenics and relatives cannot be excluded.Changes in PT surface area would not havebeen detected in the current study since theywerenot measured.If changesin PT surfacearea asymmetries were present in oursample, our results would be consistentwith changes in thickness (but not volume)of the grey matter underlying the PT. Assuggested by Barta et a! (1997b, in press),changes in surface area could occur withoutcorresponding changes in grey mattervolume beneath the surface, and could alsobe consistent with previously reportedchanges in grey matter thickness in otherheteromodal association cortical areas (i.e.dorsolateral prefrontal cortex) in schizophrenia reported by the Yale group(Selemon et a!, 1995).

Methodological issues

We took care to correct for head tilt, whichcan affect the assessment of asymmetries(Bilder et a!, 1994). Volumetric measurements were done in 3-D reconstructed imageswith simultaneous viewing of the structuresin three planes, which allowed for theexamination of image data from anyviewing orientation determined by the rater.Thus we were able to overcome the difficulties associated with recognition of structureborders in single-plane measurements.

There was a significant age differencebetween the control group and that of therelatives, with the relatives being older.Since previous studies have shown that theadult pattern of PT asymmetry is establishedby mid-gestation, and that the same degreeof PT asymmetry is present in newborns(Geschwind & Galaburda, 1985), adults(Steinmetz et a!, 1991) and cadaver brains(Steinmetz et a!, 1990), it is unlikely that the

CLINICAL IMPLICATIONS

I No planum temporale volume asymmetry abnormalities were found in schizophrenic

patients and their first-degree relatives from multiply affected families.

S This finding does not supportthe hypothesis ofan aberrant'cerebral dominance gene―

affecting temporal lobe asymmetries in schizophrenia.

U The possible presence ofabnormal asymmetry in other brain regions needs to be

explored.

LIMITATIONS

U The sample size was relatively small.

U The planum temporale surface area was not measured.

. The rater wasnot blindto sideduringthe analysis.

SOPHIAFRANGOU, MRCPsych,King'sCollegeSchoolof Medicineand Dentistry and the Institute of Psychiatry.London; 1ONMOY SHARMA, MRCPsych, THORDUR SIGMUNDSSON, MRCPsych, Institute of Psychiatry,

London;PATRICKE.BARTA,MD,GODFREYPEARLSON,MD,Departmentof PsychiatryandBehaviouralSciences,Johns Hopkins University. Baltimore, US; ROBIN M. MURRAY, DSc, King's College School of Medicine

and Dentistry and the Institute of Psychiatry.London

Correspondence: Dr S.Frangou. Department of Psychological Medicine, Institute of Psychiatry, DcCrespigny Park, London 5E5 8AF. Fax: 0171 701 9044

(First received 22 July 996, final revision 28 October 996, accepted 5 November 1996)

temporal lobe asymmetry. However, we didnot measure PT surface area where changesmay be present.

The PT is only one of the brain regionsthat show an asymmetrical pattern ofdevelopment. Lateralisation of differentbrain structures may be determined bymore than one mechanism (Habib et a!,1995). Indeed, Bilder et a! (1994) found a

loss of asymmetry in the frontal andoccipital but not the temporal lobe in firstonset schizophrenics. Therefore, our findings of normal PT volume asymmetry do notexclude the possibility of abnormalities inother brain areas, a hypothesis we arecurrently exploring in this sample.

age difference between controls and relatives

could have had any influence.The lack of significant difference in PT

volume asymmetry coefficients betweenschizophrenic patients, their relatives andcontrols may represent a true finding or atype H error. At present the effect size of PTvolume asymmetry reduction or reversal inschizophrenia is not clearly defined, but thesample size in our study is comparable tothose in previous studies where significantdifferences have been found (Table 1).

Finally, the rater was not blind to side inthe current study, possibly introducing somebias in terms of known asymmetries.

CONCLUSIONS

To our knowledge, this is the first study toaddress directly the genetic basis of PTvolume asymmetry and its association withschizophrenia in a sample of familialschizophremcs and their relatives. As far asPT volume asymmetry is concerned, ourfindings do not support Crow's hypothesisof an aberrant “¿�cerebraldominance gene―inschizophrenia responsible for loss of

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