Psychiatry Research, 52 :4 3 -53Flsevier

Magnetic Resonance Imaging Findings of Amygdala-Anterior Hippocampus Shrinkage in Male PatientsWith Schizophrenia

Alessandro Rossi, Paolo Stratta, Fabrizio Mancini, Massimo Gallucci,Paolo Mattei, Laura Core, Vittorio Di Michele, and Massimo Casacchia

Received November 18, 1992 ; first revised version received April 2, 1993; second revisedversion received June 8,1993 ; accepted July 23, 1993 .

Abstract. Recent magnetic resonance imaging (MRI) studies found abnormalitiesof medial temporal lobe and basal ganglia structures . We used an inversionrecovery (IR) protocol with the assistance of the Falairach atlas to identifyneuroanatomical regions of interest in 19 male schizophrenic patients and14 matched control subjects. The patient group showed smaller amygdala-hippocampus volume as compared with normal control subjects . This finding wasmore pronounced for the left side, although no diagnosis X side interaction waspresent. Third ventricle volume was also enlarged in schizophrenic patients .Trends toward an overall reduction of basal ganglia (striatum and lenticularnuclcus) and limbic structures and toward an increase in ventricle-brain ratiowere also seen . The study confirms previous evidence of menial temporal lobeshrinkage, more evident on the left side in a group of relapsing noninstitutional-ized male schizophrenic patients .

Key Words. Medial temporal lobe, basal ganglia, third ventricle .

Recent neuroanatomic studies have produced convincing evidence of subtlepathological changes in the brains of schizophrenic patients . These changes aremostly localized within the limbic system and, less frequently, within the basalganglia (for reviews, see McKenna, 1987 ; Reynolds, 1989 ; Buchsbaum, 1990) . Theuse of magnetic resonance imaging (MRI) has recently allowed researchers to studybrain morphology in vivo .

Investigators have found reduced volumes of the temporal lobe area (Rossi et al .,1990), superior temporal gyros (Barta et al ., 1990), and hippocampus and amygdala(Barta et al ., 1990 ; Becker et al ., 1990 ; Suddath et al ., 1990 ; Bogerts et al ., 1990a ;Shenton et al ., 1992) .

Alessandro Rossi, M.D ., is Associate Professor of Psychiatry ; Paolo Stratta, M.D ., is Staff Psychiatrist;Fahrizio Mancini, M.D ., Paolo Mattei, M.D ., and Laura Core, M.D ., are Residents in Psychiatry;Vittorio Di Michele, M.D ., is Staff Psychiatrist ; and Massimo Casacchia, M.D ., is Professor ofPsychiatry and Chairman, Department of Psychiatry, University of L'Aquila, L'Aquila, Italy . MassimoGallucci, M .D., is Neuroradiologist, Magnetic Resonance Unit, Department of Radiology, University ofL'Aquila, L'Aquila, Italy . (Reprint requests to Dr . A . Rossi, Dept . of Psychiatry, University of L'Aquila,S.M. Collcmaggio Hospital, 67100 L'Aquila, Italy .)

0165-1781,1941$07 .00 0 1994 Elsevier Science Ireland Ltd .

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Recently, Jernigan et al . (1991), who included part of the accumbens in thelenticular structure, with pallidus and putamen, reported that schizophrenic patientsshowed an increase of lenticular nucleus . Swayze et al. (1992) reported a significantenlargement in the putamen and lesser enlargement of the caudate in maleschizophrenic patients contrasted with healthy control subjects and bipolar patients .Two other MRI studies (Kelsoe et al ., 1988 ; DeLisi et al ., 1991) found larger pallidalsize among patients, although not to a statistically significant degree . The increasedsize of the basal ganglia has been interpreted as a consequence of a delay ofprogrammed synaptic elimination (Jernigan et al., 1991) and as a compensatoryresponse to a decreased input from anterior temporal, frontal, or thalamic regions(Swayze et al ., 1992) .

Among the components of the basal ganglia that have been investigated, thenucleus accumbens has received little attention, probably because it is difficult toidentify in post-mortem and MRI studies . In fact, Bogerts et al . (1985, 1990b)included the accumbens in the last ventral part of the striatum, acknowledging thatthe anatomical borders of the nucleus accumbens are problematic . However, thenucleus accumbens measure that they reported did not differ between patients andcontrol subjects . In a post-mortem study, Pakkenberg (1990) found a reducednumber of neurons in the accumbens . Because the nucleus accumbens is thedopamine target of the hippocampus and amygdala, it is postulated that this areamight play a major role in the pathophysiology of schizophrenia (Stevens and Gold,1991) .

With the aim of detecting abnormalities in the basal ganglia or limbic structures,we developed a new MRI protocol with that paid special attention to refinements inthe identification of anatomical structures such as the nucleus accumbens that havebeen difficult to delineate . Because earlier reports have suggested that morphologicalabnormalities are more prevalent in male than in female schizophrenic patients (forreview, see Castle and Murray, 1991), we confined our study to males .

Methods

Subjects . The index group consisted of 19 men who met DSM-!II criteria for schizophrenicdisorders (American Psychiatric Association, 1980) . They were recruited from among patientsadmitted to the Department of Psychiatry at the University of L'Aquila. All had beenpreviously hospitalized at least once, but treatment with neuroleptic medication enabled themto live in the community . Pertinent characteristics of the patient group were as follows : meanage, 33.42 years (SD = 7.32) ; mean height, 17284 cm (SD = 6.26) ; mean years of education,10.36 (SD = 2.26); mean age at onset, 21 .84 years (SD = 4.08), mean length of illness, 11 .57years (SD = 6.33) ; and mean neuroleptic dose in chlorpromazine equivalents, 1022.57(SD = 694.42) .

Fourteen control subjects were selected from employees of S .M. Collemaggio Hospital andmembers of the surrounding community . They were matched as closely as possible to thepatients on age and years of education (within 3 years). Their mean age was 31 .00 years(SD= 3.92), and their mean height was 170 .16 cm (SD = 5 .84) .

All subjects were right-handed according to the Edinburgh Inventory (Oldfield, 1971) .Because of movement artifacts, MRI scans for three additional patients and two additionalcontrol subjects could not be evaluated .

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MRI Protocol . All patients were examined with a 0 .25-Tesla Ansaldo MRI scanner . Aninitial 3-mm sagittal series was used for slice orientation, identifying the anterior commissure(AC)-posterior commissure (PC) line . The AC and PC are readily visible on a midsagittalinversion-recovery (IR) image (TR = 300, TE = 20) . The AGPC line was then traced on theconsole . From this line, seven subsequent coronal sections (TR = 1500 msec, TE = 38 msec,5-mm thick, I-mm interslice gap) perpendicular to the AC-PC line were taken .

These reference lines allowed us to identify the neuroanatomical structures of interest withthe aid of the Talairach atlas (Talairach and Tournoux, 1988), which has been used in severalMRI localization studies (Vanier et al ., 1987 ; Steinmetz et al ., 1989, 1990) . The atlas is helpfulin attempts to standardize brain position across subjects and thus to standardize a method ofmeasurement of specific subcortical and limbic structures .

Neuroanatomical Measurements . The central coronal slice (slice 4) was tangentposteriorly to the AC . This slice represents the VAC line . Because of the 5-mm slice thickness,its center was tangent to the AC so that 2 .5 mm overlapped the AC . This slice, which clearlyshowed the anterior amygdala and pallidus, was chosen as the reference slice (Fig . 1-d) . Slices2 and 3 in the anteroposterior (AP) direction showed the head of the caudate nucleus, theputamen, and the nucleus accumbens (Figs . I-b and I-c) . The first slice in the AP direction(Fig. I-a) showed the head of the caudate .

The slice posterior to the reference slice (slice 5 in the AP direction) showed the amygdala-hippocampus complex (Fig . 1-e) . The globus pallidus was not measured in this section becauseit could not be clearly identified . The next slice (Fig . I-f) clearly showed the mammillarybodies and the posterior hippocampal region . The temporal horns of the lateral ventricleswere visible in slices 4 and 5 but were not measured . The last slice (Fig .l-g) showed theposterior hippocampus, according to Bogerts et al . (1990a) . Table I defines the landmarksused to assess the regions of interest .

The entire brain, the lateral ventricles, and the third ventricle areas were measured in slices 4to 6 from film with a computerized analysis system (Fig . 2, left side).

The caudate nucleus, the lenticular nucleus, the putamen, the nucleus accumbens, theamygdala, and the hippocampus were identified on the brain atlas, and the structures ofinterest were traced and drawn on a transparent overlay by two of us (A-R . and F. M.) . Brainstructure areas from film and transparent overlay were obtained with a semiautomated imageanalyzer (Eidoips by Eidosoft, Milan ; a full set of information about this image-analysissystem is available from the authors on request) . Briefly, to obtain measurable images, abinarization of regions of interest was obtained through contrast enhancement (Fig . 2) .

Area measurements were made independently by two of us (A.R . and F.M .) who wereunaware of the subjects' diagnoses . The measurements used in subsequent calculations werethe average of the two evaluations . Intrarater and interrater reliahilities were high (r = 0 .92and 0 .88, respectively) .

The volumes of the gray matter structures, the whole brain, and the lateral and thirdventricles were then determined by summing these areas and multiplying them by thethickness of the slice (see Table 1) . The volumes of the subcortical gray matter and limbicstructures evaluated were then summed to obtain a global measurement of the target regions .

All volume measurements were expressed in cubic centimeters . The ventricle-brain ratio(VBR) was calculated as the ratio of the volume of the lateral ventricles to that of the brain,expressed as a percentage .

Statistical Analysis . A two-way mixed analysis of variance with a between-subjects factor ofdiagnosis (schizophrenic patients vs . control subjects) and a within-subjects factor ofhemisphere (left vs . right) was used where appropriate (Nie et al ., 1975) . A t test for unpaireddata was used for global rating and Pearson's product-moment correlation coefficient (r) wasused for correlation analysis .

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Fig. 1 . Contiguous coronal magnetic resonance (MR) sections from themost anterior (A) to the most posterior (G) level

CN = caudate nucleus. Ac = accumbens . Pu = putamen . LN = lenticular nucleus. Am = amygdala .Hi = hippocampus . Levels D, E, and F were slices where corona) brain area and ventricle-brain ratio (VBRI weremeasured (see text for further explanations] .

Table 1 . Anterior and posterior extent of the regions of interest

Note . Asterisks indicate the figures of the Talairach and Tournoux (1988) atlas that best approximated the coronalimages obtained in this report. Lenticular structure included globus pallidus and putamen . Posterior pallidus )slicebehind the 4th) was not included because of questions about measurement reliability .

Fig. 2. Binary image (left side) of the magnetic resonance image

The image is the E level (see Fig. 1) . The amygdala-anterior hippocampus outline is shown on the right side .

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Region Most anterior slice Most posterior sliceCaudate nucleus Where clearly visible Where clearly visible,

usually slice 1 usually slice 4(Fig. 73') (Fig . 79')

Putamen Putamen was measured in slice 2 only (Fig . 75') . In this slice it wasmeasured together with the nucleus accumbens because ofdifficulty in separating the two structures

Nucleus accumbens Usually slice 3 (Fig . 76-77')

Lenticular nucleus' Usually slice 3 Usually slice 4(Fig . 77-78*/ (Fig . 79')

Amygdala-anterior hippocampus Slice tangent behind Usually slice 5anterior commissure, (Fig . 80')slice 4 (Fig . 79')

Posterior hippocampus First appearance of Usually slice 7, thethe mammillary bodies, most posterior sliceusually slice 6 (Fig . 82*)(Fig . 81*)

Third ventricle Slice 5 (Fig . 79-80*) Slice 6 (Fig . 81 *)

Ventricle-brain ratio(lateral ventricularareas/coronal area x 100) Slice 4 (Fig . 78-79') Slice 6 (Fig . 81 *)

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Results

As shown in Table 2, schizophrenic patients showed smaller amygdala-anteriorhippocampus volumes (two-way mixed analysis of variance [ANOVA] group factor :F = 4.00 ; df = 1, 30 ; p < 0.05). Predetermined post hoc unpaired t tests wereconducted separately for the left and the right amygdala-hippocampus between thetwo groups . The left but not the right amygdala volume was reduced in the patientgroup (Left side : mean = 1 .08, SID =0 .21 in the schizophrenic patients ; mean = 1 .31,SD = 0.32 in the control subjects ; t = 2.37, df= 30, p = 0.025. Right side: mean =1 .11, SD =0 .25 in the schizophrenic patients ; mean = 1 .25, SD = 0 .31 in the controlsubjects ; t = 1 .44, df = 30, p = 0.15). There was a trend toward a diagnosis X sideinteraction at the amygdala-hippocampus level, even though it was not statisticallysignificant (F= 1 .89; p = 0.18). Enlargement of the third ventricle (p < 0 .05) wasalso observed in the schizophrenic group . The two-way mixed ANOVAs also showeda significant factor of side in caudate and lenticular nucleus volumes, with the leftside being smaller than the right side (caudate nucleus : F= 7 .52 ; df= 1, 27;p < 0 .01 ;lenticular nucleus : F= 8 .07 ; df= 1, 30 ; p < 0.01, respectively) .

Although statistical significance was not achieved, a trend toward a reduction oftotal gray matter volume and an increase of VBR in the schizophrenic sample wasobserved. Coronal brain volumes did not differ between groups (Table 2) . Nostatistically significant correlations at the p < 0 .01 level were seen betweenneuroanatomical and demographic variables .

Discussion

Our findings demonstrate limbic system abnormalities in schizophrenic patients,mainly due to amygdala and pes hippocampi volume reduction . Moreover, the leftside seems to have a major involvement in this reduction, although statisticalanalysis did not reveal a diagnosis X side interaction . This finding confirms previousobservations of left amygdala reduction in schizophrenia (Barta et al ., 1990; Shentonet al ., 1992) . Because of the lack of clear boundaries between the hippocampus andthe amygdala, our amygdala-hippocampus measurements probably contain the mostrostral part of the hippocampal formation as in the study of Bogerts et al . (1990a) .Our results substantially agree with those of Suddath et al . (1990) of smaller peshippocampi . Interestingly, in a post-mortem study, Reynolds (1983) reportedasymmetries of amygdala dopamine distribution in schizophrenia, with left-sidedincreases . Bogerts et al. (1990a) reported that the left posterior mesiotemporalregion, which mainly contains hippocampal tissue, was reduced among maleschizophrenic patients .

Our finding of abnormal limbic system morphology in schizophrenia is consistentwith reports of reduced cross-sectional areas in the anterior hippocampal regions ofMET scans of chronic patients (DeLisi et al ., 1988 ; Suddath et al ., 1990) and with theone study that reported reduced temporal lobe gray matter as being most pro-nounced in the central section anatomically corresponding to the part of thetemporal lobe containing the anterior hippocampus (Suddath et al ., 1989) .

Table 2. Subcortical and temporal structure dimensions in maleschizophrenic patients and male control subjects

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Note. The number of patients who could be evaluated is shown in parentheses. For3 subjects, some slices are missingdue to errors in the printout of magnetic resonance imaging films .1 . Post hoc analyses, unpaired t tests, schizophrenic patients vs . control subjects : left amygdala volume, t - 2 .37,di= 3o p < 0.05 ; right amygdala volume, t = 1 .44, NS .2. Student's t test for unpaired data : p < 0 .10 trend .

Regionalmeasure

Schizophrenicpatients(n=19)

Normalcontrols(n=14)

2-way mixedanalysis of variance

group(A)

factor

side(B)

factorA x B

interactionMean SD Mean SD

Caudate nucleus(cm 3 )Left 1 .18 0.31 (17) 1 .24 0.31 (12) F=0.98 F=7.52 F-0.81Right 1 .26 0 .30 (17) 1 .41 0.23 (12) NS p<0.01 NS

Putamen (cm 3)Left 0 .41 0 .19 (19) 0.46 0 .18 (14) F=0.84 F=1 .37 F=0.02Right 0.44 0.19 (19) 0.50 0.18 (14) NS NS NS

Nucleus accumbens(cm3 )Left 0 .12 0.04(19) 0.12 0.04(13) F=0.61 F=0.01 F=0.86Right 0 .11 0 .05 (19) 0.13 0.03 (13) NS NS NS

Lenticular nucleus(cm3)Left 1 .50 0.28(19) 1 .59 0 .36(13) F=0.57 F=8.07 F=0.04Right 1 .67 0.31 (19) 1 .74 0 .36 (13) NS p < 0 .01 NS

Amygdala-anteriorhippocampus (cm3)Left 1 .08 0.21 (18) 1 .31 0 .32(14) 1 F=4.00 F=0.17 F=1 .89Right 1 .11 0.25 (18) 1 .25 0 .31 (14) p < 0 .05 NS NS

Posterior hippocampus

(cm3 )Left 0 .95 0.17(19) 0.98 0.26(13) F=0.26 F=0.46 F=0.01Right 0.92 0.25 (19) 0.96 0.15 (13) NS NS NS

Lateral ventricles(cm 3 )Left 1 .89 1 .16(18) 1 .46 0.64(14) F=0.73 F-2.02 F = 0 .04Right 1 .80 1 .01 (18) 1 .39 0.54 (14) NS NS NS

Unpaired ttests

Third ventricle (cm 3 ) 0.67 0 .18(18) 0.52 0.12(14) t=2.62 p<0.02Coronal brain volume

(cm 3 ) 132.04 9 .88(18) 136.41 10.91 (14) t=1 .19 NS

Total gray mattervolume (cm3) 10 .18 1 .18(18) 10 .91 0.86(12)2 t=1 .81 p<0.10

Ventricle-brain ratio(i) 2.80 1 .57(18) 2.07 0.70(14)3 t=1 .61, p<0.10

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A recent PET study further suggests that abnormalities in the left medial temporalarea are correlated with the overall severity of symptoms in schizophrenia (Friston etal., 1992) . In line with this finding, the structures of the medial temporal lobe arebelieved to have a crucial role in the integration and processing of the output fromthe association cortex. Dysfunction of this system could result in the clinicalsymptoms that form the core of the schizophrenic disorder (Gray et al ., 1991 ;Roberts, 1991) . The asymmetrical pattern of the structural abnormalities describedin the present report may be explained by the asymmetrical pattern of normal braindevelopment so that a disturbance simultaneously affecting both hemispheres coulddisproportionately affect the left (dominant) one (Bracha, 1991 ; Roberts, 1991) .However, our failure to detect a diagnosis X side interaction does not support the"latcralization hypothesis" of schizophrenia (Weinberger et al ., 1991) .

Notwithstanding the interest in the role of the limbic system in schizophrenia andevidence of somewhat localized pathological changes of the temporal lobe, post-mortem findings involving other areas of the brain have also been reported (Benes etal., 1986 ; Pakkenberg, 1987 ; Bogerts et al ., 1990h) . In two related post-mortemstudies, Heckers et al . found increased striatal volume (1991) but no significantvolume reduction of amygdala and hippocampal formation (1990) in schizophrenicpatients .

The well-established VBR increase observed in the majority of computedtomographic (C]') studies suggests that the morphological abnormalities are notlimited to a single site (Shelton and Weinberger, 1986) . Our findings seem to be inline with these observations because even though the amygdala region seems themost affected gray matter area, other target regions show a reduction in volume . Asa matter of fact, we report a robust trend toward a VRR increase . The failure todetect an even greater VBR increase may be due to our measures of ventricular areaslimited to the central aspect (slices 4-6 of our MRI scans) . Nonetheless, our report ofan enlargement of the third ventricle is in agreement with a recent MRI study(Suddath et al ., 1990) and with the CT literature (Shelton and Weinberger, 1986) .This finding is consistent with aplasia or atrophy of thalamic or hypothalamicelements. Zipursky et al . (1992) recently reported a widespread reduction of graymatter in schizophrenia, seriously challenging the idea of focal dysplasia .

Contrary to other recent MRI studies (Jernigan et al ., 1991; Swayze et al., 1992),we were unable to confirm an increase in basal ganglia structures in schizophrenia .Despite differences in MRI scanning procedures, our failure to detect an increase instriatal structures may be due to differences in our subjects such as hormonal statusor neuroleptic exposure . These factors should be carefully assessed before striatalchanges are posited as primary factors in the pathophysiology of schizophrenia(Jernigan et al., 1991 ; Swayze et al ., 1992) . Alternatively, abnormal reinnervation asa response to a "lesion" in mesolimhic structures (Stevens, 1992) may be postulatedas a mechanism that elicits a striatal increase in some patients but not in others (suchas the ones we studied), for whom other areas at different times could be involved .

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Nevertheless, converging evidence suggests that a disruption of the limbic-striatalconnection may be key to the development of schizophrenia . As suggested byStevens (1992), much work should be done to identify possibly "reactive" neuro-biological events leading to aberrant synaptic expansion secondary to damage inlimbic structures . Although we did not observe shrinkage of the nucleus accumbensas suggested by a recent post-mortem neuroanatomical study (Pakkenberg, 1990),the finding of amygdala shrinkage suggests that the accumbens-amygdala circuitry isdisturbed (Cools and Ellembroek, 1991) .

We believe that schizophrenia has to be considered not as a single entity but ascluster of disorders, each having its own characteristic neural, cognitive, andphenomenological disturbances deriving from subtle deficits in distinct parts of thelimbic-striatal circuitry . Further work is needed for a better characterization of theextent and localization of the pathological anatomy in schizophrenia . If these studiescontribute to bridging the gap that now separates neuroanatomical from geneticresearch (Jones and Murray, 1991), our neurobehavioral knowledge of schizo-phrenia would be greatly enhanced .

Acknowledgment . The research reported was supported in part by a grant M .P .I . 40%(1991, 1992) to Prof. Massimo Casacchia.

References

American Psychiatric Association . DSM-III.Diagnostic and Statistical Manual of MentalDisorders . 3rd ed. Washington, DC : APA, 1980 .

Barta, P .E . ; Pearlson, G.D.; Powers, R .E . ; Richards, S .S . ; and Tune, L .E. Auditoryhallucinations and smaller superior temporal gyros volume in schizophrenia . AmericanJournal of Psychiatry, 147 :1457-1462, 1990 .

Becker, T . ; Elmer, K,; Mechela, B . ; Schneider, F . ; Taubert, S . ; Schroth, G . ; Grodd, W . ;Bartels, M . ; and Beckmann, H . MRI findings in medial temporal lobe structures inschizophrenia. European Neuropsychopharmacology, 1 :83-86, 1990 .

Benes, F .M . ; Davidson, J . ; and Bird, E .D. Quantitative cytoarchitectural studies of thecerebral cortex of schizophrenics . Archives of General Psychiatry, 43 :31-35, 1986 .

Bogerts, B . ; Ashtari, M . ; Degreef, G . ; Alvir, J.M . ; Bilder, R . ; and Lieberman, J.A .Reduced temporal limbic structure volumes on magnetic resonance images in first episodeschizophrenia. Psychiatry Research : Neuroimaging, 35 :1-13, 1990a .

Bogerts, B . ; Falkai, P .; Haupts, M .; Greve, B . ; Ernst, S . ; Tapernon-Franz, U . ; andHeinzmann, U . Post-mortem volume measurements of limbic system and basal gangliastructures in chronic schizophrenics . Schizophrenia Research, 3 :295-301, 1990b .

Bogerts, B . ; Meertz, E .; and Schonfeld-Baush, R . Basal ganglia and limbic systempathology in schizophrenia . Archives of General Psychiatry, 42 :784-791, 1985 .

Bracha, H .S. Etiology of structural asymmetry in schizophrenia : An alternative hypothesis .Schizophrenia Bulletin, 17 :551-553, 1991Buchsbaum, M .S. The frontal lobes, basal ganglia, and temporal lobes as sites for

schizophrenia . Schizophrenia Bulletin, 16 :379-389, 1990.Castle, D .J., and Murray, R.B. The neurodevelopmental basis of sex differences in

schizophrenia . Psychological Medicine, 21 :565-575, 1991 .Cools, A .R., and Ellembroek, B . The limbic-striatal interaction : A seesaw rather than a

tandem. (Commentary) Behavioral and Brain Research, 14 :22, 1991 .

52

DeLisi, L.E, ; Dauphinais, I.D . ; and Gershon, E.S. Perinatal complication and reduced sizeof brain limbic structures in familial schizophrenia. Schizophrenia Bulletin, 14 :185-191, 1988 .

DeLisi, L.E . ; Hoff, A . ; Schwartz, J .E . ; Shields, G.W . ; Halthore, S.N. ; Gupta, S .M .{ Henn,F.A . ; and Anand, A .K . Brain morphology in first-episode schizophrenic-like psychoticpatients : A quantitative magnetic resonance imaging study . Biological Ps.vchiatry, 29:159-175,1991 .

Friston, K.J . ; Liddlc, P .F . ; Frith, C .D . ; Hirsch, S.R . ; and Frackowiak, R .S .J . The leftmedial temporal region and schizophrenia . Brain, 115 :367-382, 1992 .

Gray, J.A . ; Feldon, J .; Rawlins, J .N .P . ; Hemsley, D.R . ; and Smith, A.D. Theneuropshychology of schizophrenia . Behavioral and Brain Research, 14:1-84, 1991 .

Heckers, S . ; Heinsen, H . ; Heinsen, Y.C . ; and Beckmann, H . Limbic structures and lateralventricle in schizophrenia . Archives of General Psychiatry, 47:1016-1022, 1990 .

Heckers . S . : Heinsen, H . ; Heinsen, Y.C . ; and Beckmann, H, Cortex, white matter and basalganglia in schizophrenia : A volumetric postmortem study. Biological Psychiatry, 29:556-566,1991 .Jernigan, T.L. ; Zisook, S .; Heaton, K .; Moranville, J .T . ; Hesselink, J.R . ; and Braff, D .L .

Magnetic resonance imaging abnormalities in lenticular nuclei and cerebral cortex inschizophrenia. Archives of General Psychiatry, 48:881-890, 1991 .Jones, P ., and Murray, R.M. The genetics of schizophrenia is the genetics of

neurodevelopment . British .lournal of Psychiatry, 158:615-623, 1991 .Kelsoc, J.R . ; Cadet, J.L . ; Pickar. D . ; and Weinberger, D.R. Quantitative ncuroanatomy in

schizophrenia . Archives of General Psychiatry, 45:533-541 . 1988 .McKenna, P .J. Pathology, phenomenology and the dopamine hypothesis of schizophrenia .

British .lournal of Psychiatry, 151 :288-301, 1987 .Nie, N.H . ; Hull, C.H . ; Jenkins, G.J . ; Stcinbrenner, K . ; and Bent, D.H ., eds. SPSS :

Statistical Package for Social Science. 2nd ed . New York: McGraw-Hill International BookCo., 1975 .Oldfield, R .C. The assessment and analysis of handedness : The Edinburgh Inventory .

Neuropsychologia, 9:97-113, 1971 .Pakkenberg, B . Post-mortem study of chronic schizophrenic brains . British Journal of

Psychiatry, 151 :744-752, 1987 .Pakkenberg, B . Pronounced reduction of total neuron number in mediodorsal thalamic

nucleus and nucleus accumbens in schizophrenics . Archives of General Psychiatry, 47 :1023-1028, 1990 .Reynolds . G .P. Increased concentrations and lateral asymmetry of amygdala dopamine in

schizophrenia . Nature, 305:527-529, 1983 .Reynolds, G .P. Beyond the dopamine hypothesis . British Journal of Psychiatry, 155 :305-

316, 1989 .Roberts. G.W. Schizophrenia : A neuropathological perspective . British Journal of

Psychiatry, 158:8-17, 1991 .Rossi, A . ; Stratta, P .; D'Albenzio, L . ; Tartaro . A . ; Schiazza, G . : Di Michele, V . ; Bolino, F . :

and Casacchia, M . Reduced temporal lobe areas in schizophrenia : Preliminary evidence froma controlled multiplanar magnetic resonance imaging study . Biological Psychiatry, 27:61-68,1990 .

Shelton, R.C ., and Weinberger, D .R . X-ray computerized tomography studies inschizophrenia : A review and synthesis . In : Nasrallah, H .A ., and Weinberger, D .R ., eds. TheNeurology of Schizophrenia. Handbook of Schizophrenia. Vol . 1 . Amsterdam : Elsevier, 1986 .pp. 207-250 .

53

Shenton, M .F . ; Kikinis, R . ; Jolesz, F .A. ; Pollak, S.D . ; Le May, M . ; Wible, C.G . ; Hokama,H .; Martin, J . ; Metcalfe, D .; Coleman, M .; and McCarley, R .W. Abnormalities of the lefttemporal lobe and thought disorder in schizophrenia . New England Journal of Medicine,327:604-612, 1992.

Steinmetz, H . ; Furst, G . ; and Freund, H .J . Cerebral cortical localization : Application andvalidation of proportional grid system in MR imaging . Journal of Computer AssistedTomography, 13 :10-19, 1989 .Steinmetz, H . ; Furst, G .; and Freund, H .J . Variation of perisylvian and calcarine anatomic

landmarks within stereotaxic proportional coordinates . American Journal of Neuroradiology,11 :1123-1130,1990 .

Stevens, J.R. Abnormal reinnervation as a basis for schizophrenia : A hypothesis . Archivesof General Psychiatry, 49:238-243, 1992 .

Stevens, J.R., and Gold, J .M. What is schizophrenia'? (Commentary) Behavioral and BrainSciences, 14:50-51, 1991 .Suddath . R.L . ; Casanova, M.F. ; and Goldberg, T.E. Temporal lobe pathology in

schizophrenia : A quantitative magnetic resonance imaging study . American Journal ofPsychiatry, 146:464-472, 1989 .Suddath, R .L . ; Christison, G.W . ; Torrey, E.F . ; Casanova, M .F . ; and Weinberger, D .R .

Anatomical abnormalities in the brain of monozygotic twins discordant for schizophrenia .New England Journal of Medicine, 322:789-794, 1990 .Swayze, V .W. II . ; Andreasen, N.C . ; Alliger, R .J . ; Yuh, W.T.C . ; and Ehrhardt, J .C .

Subcortieal and temporal structures in affective disorder and schizophrenia : A magneticresonance imaging study . Biological Psychiatry, 31 :221-240, 1992 .

Talairach, J ., and Tournoux, P . Co-planar Stereotaxic Atlas of the Human Brain . Berlin :Springer, 1988 .

Vanier, M . ; Ethier, R . ; Clark, J . ; Peters, T.M . ; Olivier, A . ; and Melanson, D . Anatomicalinterpretation of MR scans of the brain . Magnetic Resonance Medicine, 4:185-188, 1987 .Weinberger, D.R . ; Suddath, R .1 . . ; Casanova, M .F . ; Torrey, E .F . ; and Kleinman, J .E.

Crow's "Lateralization hypothesis" for schizophrenia . Archives of General Psychiatry, 48:85,1991 .Zipursky, R.B . ; Lim, K.O . ; Sullivan, E . V . ; Brown, B . W . ; and Pfefferhaum, A. Widespread

cerebral gray matter volume deficits in schizophrenia . Archives of General Psychiatry, 49:195-205, 1992 .