prefrontal cortex, negative symptoms, and schizophrenia: an mri...

Ž .Psychiatry Research: Neuroimaging Section 108 2001 65�78

Prefrontal cortex, negative symptoms, andschizophrenia: an MRI study

Cynthia G. Wiblea,b,c,d, Jane Andersona,b,c,d, Martha E. Shentona,b,c,d,Ashley Kricuna,b,c,d, Yoshio Hirayasua,b,c,d, Shin Tanakaa,b,c,d,James J. Levitta,b,c,d, Brian F. O’Donnella,b,c,d, Ron Kikinise,f,

Ferenc A. Jolesze,f, Robert W. McCarley a,b,c,d,�

aDepartment of Psychiatry, Har�ard Medical School, Boston, MA, USAbBrockton Veterans Affairs Medical Center, Brockton, MA, USA

cMassachusetts Mental Health Center, Boston, MA, USAdMcLean Hospital, Belmont, MA, USA

eDepartment of Radiology, Har�ard Medical School, Boston, MA, USAfMRI Di�ision, Surgical Planning Laboratory, Brigham and Women’s Hospital, Boston, MA, USA

Received 26 January 2001; received in revised form 26 July 2001; accepted 9 August 2001

Abstract

The present study measured prefrontal cortical gray and white matter volume in chronic, male schizophrenicsubjects who were characterized by a higher proportion of mixed or negative symptoms than previous patients thatwe have evaluated. Seventeen chronic male schizophrenic subjects and 17 male control subjects were matched on age

Ž . Ž .and handedness. Regions of interest ROI were measured using high-resolution magnetic resonance MRacquisitions consisting of contiguous 1.5-mm slices of the entire brain. No significant differences were found betweenschizophrenic and control subjects in mean values for prefrontal gray matter volume in either hemisphere. However,right prefrontal white matter was significantly reduced in the schizophrenic group. In addition, right prefrontal graymatter volume was significantly correlated with right hippocampal volume in the schizophrenic, but not in the controlgroup. Furthermore, an analysis in which the current data were combined with those from a previous study showedthat schizophrenic subjects with high negative symptom scores had significantly smaller bilateral white mattervolumes than those with low negative symptom scores. White matter was significantly reduced in the righthemisphere in this group of schizophrenic subjects. Prefrontal volumes were also associated with negative symptomseverity and with volumes of medial�temporal lobe regions � two results that were also found previously in

� Corresponding author. Psychiatry Service, 116A, Brockton VA Medical Center, 940 Belmont Street, Brockton, MA 02401,USA. Tel.: �1-508-583-4500, ext. 2479; fax: �1-508-586-0894.

Ž .E-mail address: robert [email protected] R.W. McCarley .�

0925-4927�01�$ - see front matter � 2001 Elsevier Science Ireland Ltd. All rights reserved.Ž .PII: S 0 9 2 5 - 4 9 2 7 0 1 0 0 1 0 9 - 3

( )C.G. Wible et al. � Psychiatry Research: Neuroimaging 108 2001 65�7866

schizophrenic subjects with mostly positive symptoms. These results underscore the importance of temporal�prefron-tal pathways in the symptomatology of schizophrenia, and they suggest an association between prefrontal abnormali-ties and negative symptoms. � 2001 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: White matter; Temporal lobe; Hippocampus; Orbitofrontal cortex

1. Introduction

Frontal lobe abnormalities have been hypothe-sized to contribute to the schizophrenic syn-drome. Frontal functions such as attention, work-ing memory, eye movement, judgment and insightare thought to be impaired in schizophrenic

Žpatients Mesulam, 1981; Damasio and VanHoesen, 1983; Mesulam, 1990; Goldman-Rakicand Friedman, 1991; Anderson et al., 1994; Paus,

.1995; Petit et al., 1995 . Both structural and phys-iological frontal abnormalities have been re-ported in schizophrenic patients, but the findingshave often been contradictory. Magnetic reso-

Ž .nance imaging MRI studies have found reducedvolume in the frontal lobe. However, this findinghas not been consistently replicated. Table 1 con-tains a summary of prefrontal MRI findings inschizophrenia; also see recent reviews of MRstudies of schizophrenia for a more detailed dis-

Žcussion of frontal findings Shenton et al., 1997,.2001; McCarley et al., 1999 . Inconsistent findings

across studies could be attributed to the diversemethodologies used, including differences in fac-tors such as MR image resolution, segmentationprocedures, subject matching variables, and thesymptom profiles of the patient group.

The present study measured prefrontal grayand white matter in closely matched groups ofschizophrenic subjects and normal control sub-jects using quantitative volumetric techniques andhigh resolution MRI scans. The study was de-signed to be similar in MRI methods to a previ-ous study of prefrontal cortex volume in chronic

Ž .schizophrenics Wible et al., 1995 in which novolume differences were found between groups.However, the schizophrenic subjects for the pres-ent study were chosen from outpatient commu-

nity residences and therefore consisted of a higherproportion of subjects showing negative symp-

Žtoms either the mixed or negative symptom rat-.ing relative to the previous study, which drew on

an acutely hospitalized sample.Temporal lobe structures such as the amygdala,

hippocampus, entorhinal cortex, parahippocampalgyrus, and superior temporal gyrus have beenshown to be abnormal in schizophrenic subjects,

Žespecially on the left side Shenton et al., 1992,.1997; McCarley et al., 1999 . These temporal lobe

structures are highly interconnected with the pre-Žfrontal cortex Goldman-Rakic et al., 1984;

.Pandya and Yeterian, 1990; Wible et al., 1995 ,and in a previous study we observed volume cor-relations between prefrontal and temporal re-gions in schizophrenic subjects that were not pres-ent in control subjects. Such volume correlationsare suggestive of a functional system that ispathological in the schizophrenic brain, and wepredicted that these correlations would also befound in the current subject group.

Several negative symptoms of the schizophrenicsyndrome are similar to those symptoms present

Žafter frontal lobe damage e.g. attentional defic-.its, lack of insight into behavior . Clinical mea-

sures of negative, but not positive symptoms werecorrelated with prefrontal volume measures inthe schizophrenic group of the previous study. Wepredicted that these same clinical correlationswould be present in the current study.

2. Methods

2.1. Subjects

MR scans were obtained from 17 schizophrenicand 17 right-handed male control subjects.

( )C.G. Wible et al. � Psychiatry Research: Neuroimaging 108 2001 65�78 67

Table 1A summary table of MRI studies of prefrontal cortex in schizophrenia

Reference Slice thickness CN, SZŽ .number

Studies showing differences in frontal lobe area or �olumebetween schizophrenic and control subjectsAndreasen et al., 1986 10 mm 49, 38

Ž .DeMyer et al., 1988 10 mm 2 slices 24, 24Rossi et al., 1988 10 mm, 5 mm 12, 12

Ž .Stratta et al., 1989 10 mm 8 axial , 20, 20Ž .5 mm 1 midsag.

Jernigan et al., 1991 5 mm, 2.5 gap 24, 42Breier et al., 1992 3 mm 29, 44

Ž .Raine et al., 1992 10 mm 12 coronal 19�18,Ž .1 midsag., 1 axial 17

Ž .Zipursky et al., 1992 5 mm, 2.5 gap 7 slices 20, 22Buchanan et al., 1993 3 mm 30, 41

Ž .Harvey et al., 1993 5 mm 20 slices 34, 48Andreasen et al., 1994 1.5 mm 90, 52Bilder et al., 1994 3.1 mm 51, 70Schlaepfer et al., 1994 5 mm 60�27,

46Ž .Zipursky et al., 1994 3 mm 22 slices 20, 22

Nopoulos et al., 1995 1.5 mm 24, 24Woods et al., 1996 5 mm 19, 19

Ž .Marsh et al., 1997 3 mm 22 slices 52, 56Woodruff et al., 1997 5 mm 43, 42Ohnuma et al., 1997 4 mm 10, 10Gur et al., 1998 5 mm 17, 40Buchanan et al., 1998 1.5 mm 24, 18

Ž .Sullivan et al., 1998 5 mm 2.5 mm gap 73, 71�62

Goldstein et al., 1999 3.1 mm 26, 29Staal et al., 2000 1.6 mm 32�16,

16Szeszko et al., 1999 3.1 mm 26, 19Sanfilipo et al., 2000 2.8 mm 29, 53Gur et al., 2000 1 mm 81, 70

Studies showing no differences in frontal lobesSmith et al., 1987 8 mm, 12 mm 21, 29

Ž .Kelsoe et al., 1988 10 mm 1 midsag 14, 24Ž .Uematsu and Kaiya, 1989 10 mm 8 slices 17, 49Ž .Suddath et al., 1989 10 mm 12 slices 17, 17Ž .Rossi et al., 1990 8 mm 7�8 slices 13, 17

Nasrallah et al., 1990 3 mm, 5 mm 35, 56Andreasen et al., 1990 10 mm 47, 54

Ž .Blackwood et al., 1991 12 mm 10 slices 33, 28DeLisi et al., 1991 5 mm, 2 mm gap 20, 45Bornstein et al., 1992 5 mm, 5 mm gap 52, 72Kawasaki et al., 1993 5 mm 10, 20

Ž .Egan et al., 1994 10 mm 12 slices 16, 16Vita et al., 1995 5 mm, 2 mm gap 15, 19


Ž .Table 1 Continued

Reference Slice thickness CN, SZŽ .number

Turetsky et al., 1995 5 mm 77, 71Ž .Vita et al., 1995 5 mm 2 mm gap 15, 19

Corey-Bloom et al., 1995 5 mm, 2.5 mm gap 28, 30Ž .Wible et al., 1995 1.5 mm 36 slices 15, 14

Baare et al., 1999 1.2 mm 14, 14Lawrie et al., 1999 1.8 mm 30, 20�

100 high risk

The table shows the reference, the resolution of the MRI methods in terms of number of slices used to assess the prefrontalŽ . Ž .cortex, and the number of control CN and schizophrenic SZ subjects.

Schizophrenic subjects were recruited from theBrockton Veterans Affairs Medical Center; onewas hospitalized at the time of recruitment, 16were in VA community residences, and all werereceiving neuroleptic medication. Control sub-jects were recruited through newspaper advertise-ments. Patient diagnoses were made in accordwith the Diagnostic and Statistical Manual of

Ž .Mental Disorders DSM-III-R , on the basis ofchart review, and from information obtained fromadministration of the Schedule for Affective Dis-

Žorders and Schizophrenia Spitzer and Endicott,

.1978 . Subjects were admitted to the study if theywere between the ages of 20 and 55 years with nohistory of electroconvulsive shock treatment, neu-rologic illness, or steroid use, and no lifetime

Žhistory of drug�alcohol addiction or abuse DSM-.III-R within the last 5 years. Control subjects

were also excluded if they had a history of psychi-atric illness in themselves or in their first-degreerelatives.

The schizophrenic and control subjects wereŽ .matched as a group on age and handedness, and

there were no statistically significant differences

Table 2Ž .Subject characteristics mean and standard deviation and probability level of a one-way ANOVA test for the variables when

appropriate

Schizophrenic Control SignificanceŽ .one-way ANOVA

Number of subjects 17 17Ž .Age at test years 44 40 F�0.004, d.f.�1,31,

P�0.950Handedness 0.80 0.78 F�0.006, d.f.�1,28,

P�0.939Parental SES 3.18 2.35 F�5.07, d.f.�1,32,

�P�0.031WAIS-R information 11.75 10.53 F�2.07, d.f.�1,31,

P�0.161Duration 20Ž .years since onset

Ž . Ž .Total SANS score S.D. 11 4Range of SANS scores 4�18

Ž . Ž .Total SAPS score S.D. 8 4Range of SAPS score 1�15

�Signifies that the probability level was significant.


between the two groups in height, weight, headcircumference, or scores on the WAIS-R infor-

Ž .mation subscale Wechsler, 1981 . There was adifference in socioeconomic status of the familyof origin. See Table 2 for the means and standard

Ž .deviations S.D. of subject characteristics, includ-Ž .ing the mean chlorpromazine CPZ equivalents.

All subjects signed written informed consent priorto study participation. No subjects were in com-

Žmon with the previous prefrontal study Wible et.al., 1995 .

2.2. Clinical e�aluations

Three instruments were used to assess symp-toms: The Scale for the Assessment of Positive

Ž .Symptoms Andreasen, 1984 ; the Scale for theŽAssessment of Negative Symptoms Andreasen,

. Ž1981 ; and the Thought Disorder Index Johnston.and Holzman, 1979 . In the Andreasen classifica-

tion, 11 of the patients were characterized ashaving mixed symptoms, four had mainly positivesymptoms, and two had mainly negative symp-toms.

It should be noted that negative symptoms inthis study were measured using the SANS scale,not the Schedule for the Deficit Syndrome. TheDeficit Syndrome Scale differs from the SANSscale in that the presence or absence of negativesymptoms is considered independently of psy-chotic symptoms and that the symptoms must be

Ž .enduring features Kirkpatrick et al., 1989 .

2.3. MRI methodology

All MR scans were acquired at the Brighamand Women’s Hospital with a 1.5-T General Elec-

Žtric SIGNA System GE Medical Systems, Mil-.waukee, WI . The MR methodology is described

Ž .in detail elsewhere Shenton et al., 1992 , andhence will be only briefly described here. For themeasurement of prefrontal gray and white matter

Ž .regions of interest ROI , a three-dimensionalFourier transform spoiled gradient-recalled ac-

Ž .quisition in steady state 3DFT SPGR was ac-quired throughout the entire brain and reformat-ted into 124 contiguous 1.5-mm coronal slices.The SPGR images were obtained using the fol-

Ž .lowing parameters: echo time TE �5 ms, repe-Ž .tition time TR �35 ms, one repetition, nutation

angle�45�, field of view�24 cm, acquisition ma-trix�256�256�124, voxel dimensions�0.9375�0.9375�1.5 mm.

For the measurement of the intracranial con-Ž .tents, 108 54 for each echo contiguous double-

echo spin-echo 3-mm axial slices were obtainedthroughout the extent of the brain. Imagingparameters were: TE�30 ms, TR�3000 ms, fieldof view�24 cm, acquisition matrix�256�256,voxel dimensions�0.9375�0.9375�3 mm. Nogross abnormalities were found in the scans whenthey were evaluated by a clinical neuroradiologist.

2.4. Image processing

The image-processing stages were different forthe whole brain vs. the individual region of inter-

Ž .est ROI measurements. The image processingfor the ROI measurements on the SPGR scans

Ž .proceeded in several stages. 1 The SPGR imagesŽ .were filtered to reduce noise Gerig et al., 1990 .

Ž .2 The SPGR images were segmented using theŽ .iterative expectation�maximization EM algo-

rithm. This algorithm combines the statisticalclassification of tissue classes with the automaticidentification of intensity inhomogeneities in theimages. The EM segmenter alternates two com-putational stages. In one stage, the spatial inten-sity inhomogeneities in the images are estimated,and then in a second stage, this estimate is usedto improve the accuracy of the tissue classifica-

Žtion. An initial semi-automated segmentation thealgorithm used for segmentation in our previous

.articles was used as a starting point or as input tothe EM segmenter, and then the algorithm im-proved the segmentation in several iterations of

Ž .the two steps Wells et al., 1996 . The segmenta-tions computed using this algorithm were moreconsistent in estimating tissue classes than thesemi-automated segmentation procedures whenthe segmentation was compared among five ratersŽ . ŽWells et al., 1996 . In previous articles Wible et

.al., 1995 , the measurement of the gray�whitematter volume in a cortical region required sliceby slice editing of the boundary on each slice. Thesegmentations obtained using the EM segmenter


Fig. 1.


Ž .required much less editing. 3 The results of thesegmentation were then superimposed on theoriginal SPGR image and edited using an image-editing program, slice by slice, on the computerworkstation to exclude extraneous tissue from thegray�white matter segmentation, and to assignthe left and right lobes to separate tissue classes.The slice editor contained algorithms to performmanual drawing of ROI, connectivity, island re-moval, erosion and dilation of tissue classes, acolor editor to assign colors to different ROI, anda magnifier to magnify the image to a user-chosenlevel of magnification. The current version of this

Ž .image editor Gering et al., 1999 is described onour web pages at http:��splweb.bwh.harvard.

Ž .edu:8000�pages�papers�slicer�index.html. 5 Adividing cubes algorithm was used to reconstructthe segmentation to allow for a three-dimensional

Ž .view of each tissue class Cline et al., 1988, 1990 .The voxels for each tissue class were summed tocompute the volume for each slice and the cumu-lative volume.

The image-processing procedures for the mea-Žsurement of intracranial content used to com-

.pute the relative volume measurements were de-Žscribed in detail, in a previous study Shenton et

.al., 1992 . The 3-mm double-echo axial scans wereused for this measurement, and the image pro-cessing required some of the same algorithms asthose used in measurement of the specific pre-frontal ROI, including a preprocessing filter, andalgorithms for segmentation, connectivity, three-dimensional reconstruction and visualization, andan algorithm for calculating volume.

2.5. Specific brain regions of interest

The gray and white matter of the prefrontalcortex was measured using the same landmarks as

Ž .in our previous study Wible et al., 1995 . Theposterior boundary of the gray matter coincided

with the separation of frontal and temporal lobeareas as illustrated in Fig. 1A,B. The most poste-rior slice on which we measured prefrontal graymatter is shown in Fig. 1A in relationship to theventricles. Fig. 1B shows a three-dimensional re-construction of the white matter in relationship tothe ventricles and the most posterior gray matterslice. Reliability for the gray and white mattervolumes is discussed below.

2.6. Reliability of image-processing techniques

2.6.1. Intra-rater reliability for the frontal lobe�olumetric measures

The 34 cases were first segmented by CGW.Intra-rater reliability was assessed using the samefour pre-selected representative slices throughoutthe frontal lobe for 10 cases. The intraclass corre-lation was r �0.80.i

2.6.2. Inter-rater reliability for the �olumetricmeasures

Inter-rater reliability for two additional raterswas also obtained for the same 10 cases and wasr �0.84.i

2.7. Statistical analyses

Left and right volumes of prefrontal gray andwhite matter were analyzed using a multivariate

Ž .analysis of variance MANOVA with the vari-Ž .ables group schizophrenic vs. control , tissue class

Ž . Ž .white or gray matter , and side right or left . AnŽ .analysis of covariance ANCOVA was also used,

and the factors analyzed in the MANOVA werecovaried with age. Analyses were computed sepa-rately for absolute volumes, and for relativevolumes � the latter corrected for head size bydividing the absolute volume by the volume of theintracranial contents and multiplying by 100.

Fig. 1. The most posterior slice in which prefrontal gray matter was measured in relationship to the ventricles and the white matter.Panel 1A: left lateral view of the most posterior slice in which gray matter was measured, shown in relationship to the ventricleswith segmented prefrontal gray matter shown in green overlay on the MRI slice. Panel 1B: left lateral view of a three-dimensionalreconstruction of the prefrontal white matter in relationship to the ventricles and to the slice shown in Panels A and B.


Volumetric data were available for several tem-poral lobe structures for the subjects used in this

Ž .study Anderson et al., submitted . The hypothe-sis guiding the examination of the relationshipbetween volumes of prefrontal and temporal ROIin patients with left-lateralized temporal lobeabnormalities was that prefrontal�temporal cor-relations would be significant in schizophrenic,but not control subjects.

Univariate correlation coefficients were alsocomputed, for comparison, for right temporal lobestructures and right prefrontal gray and whitematter. Correlations were also performed, forschizophrenic patients only, between clinical mea-sures and prefrontal left and right, gray and whitematter, to assess the degree of associationbetween symptomatology and prefrontal volumemeasurements.

2.8. Analyses combining current data with pre�iouslypublished prefrontal data

ŽThe patient groups from the previous Wible et.al., 1995 and current studies were combined and

redivided into groups based on symptom profiles.This was done to examine the relationshipbetween frontal volumes and negative symptoms.

Ž .The Z-score for each relative prefrontal volumemeasure was computed for each patient by usingthe mean and S.D. of the corresponding controlgroup for that patient. Z-scores were used be-cause we were combining patients from differentstudies with different control groups. The subjectsthus had to be matched to their correspondingcontrol groups, and this necessitated the use ofZ-scores. The patient group was then ranked bythe total SANS score and divided into two equalgroups of patients, one group with the lowerSANS scores and the other with the higher SANSscores. The dividing SANS score was 10. Notethat the SANS score for one patient from theprevious study was not available. These Z-scoremeasures were then subjected to analyses.

Table 3Means and standard deviations of prefrontal left and right,gray and white volumes for schizophrenic and control subjects

Absolute Relative Number ofvolume volume slices

Left frontal gray matterŽ . Ž .Schizophrenia 68.9 8.1 4.5 0.44 36Ž . Ž .Control 73.8 12.0 4.7 0.65 37

Left frontal white matterŽ . Ž .Schizophrenia 22.6 2.2 1.5 0.12 24Ž . Ž .Control 24.2 4.2 1.5 0.18 24

Right frontal gray matterŽ . Ž .Schizophrenia 68.1 8.6 4.5 0.51 35Ž . Ž .Control 72.7 12.2 4.6 0.68 35

Right frontal white matterŽ . Ž .Schizophrenia 22.2 2.0 1.5 0.15 24Ž . Ž .Control 26.0 4.5 1.7 0.24 24

Also shown is the mean number of MRI slices used toassess each measure.

3. Results

3.1. Prefrontal �olume measures

In the present sample, control andschizophrenic subjects had similar mean values

Žfor gray, but not white matter volume see Table.3 . The results derived from relative measures

showed the same pattern of statistical significanceas those derived from absolute measures. Forbrevity, only the results of the relative measures

Žwill be reported in the text relative and absolutevolumes, as well as mean number of slices used,

.are reported in Table 3 . The MANOVA showeda three-way interaction between group, tissue,

Ž .and side F�7.30, d.f.�1,32, P�0.01 . Therewere no two-way interactions. Follow up t-testsshowed significant differences between groups in

Žright prefrontal white matter t��2.85, d.f.�.1,32, P�0.008 . An ANCOVA was done with the

same factors using subject age as a covariate; thisanalysis showed a pattern of significance similarto that described above.


3.2. Prefrontal�temporal uni�ariate Pearsonproduct-moment correlations

Note that correlations are reported only if val-ues were consistently significant using both abso-lute and relative volume measures. Volumes ofright prefrontal gray matter and right posterioramygdala�hippocampal complex showed high

Žpositive correlations for schizophrenic subjects r�0.73, P�0.001 abs. vol.; r�0.68, P�0.004 rel.

.vol. . This correlation was not significant in theŽcontrol group vol.; r�0.48, P�0.118 abs. vol.;

.r�0.43, P�0.17 rel. vol. .

3.3. Prefrontal ROI-clinical correlations

The correlation of total SANS scores and leftfrontal gray matter volume was significant in

Žschizophrenic subjects r��0.50, P�0.043 abs..vol.; r�0.52, P�0.033 rel. vol. . The correlations

between SANS score and white matter volumesdid not reach significance in the current sampleŽ r��0.29, P�0.26 abs. vol., left hemisphere;

.r��0.07, P�0.78 abs. vol., right hemisphere .Thought Disorder Index scores did not correlatewith any measure of prefrontal cortex volume.

3.4. Analyses of combined data from the currentstudy and a pre�iously published study

The same analysis described above for the cur-rent subject sample was performed on the com-bined data from current and previously publishedprefrontal volumes of schizophrenic and controlgroups. The previous study used the same generalscanning parameters and the image editor wasalso the same as used in the current study. Thesegmentation algorithms differed between the twostudies; however, the final editing of the segmen-tation was done by hand in both studies. Nosignificant differences were found between com-

Žbined groups combined schizophrenia, n�31,.and combined control, n�32 for any of the

Žprefrontal measures right or left gray or white.matter .

The relative prefrontal volume measures forthe combined schizophrenic group were trans-formed into Z-scores and the combined group

Ž .Fig. 2. Relative volumes of average left and right combinedprefrontal white matter for schizophrenic subjects with highand low SANS scores. The subject data shown are from acombination of the current study and our previous study ofprefrontal volume in schizophrenia. The low and high SANSgroups were determined by ranking all schizophrenic subjectsand doing a median split to obtain two groups.

was split into halves according to SANS scoresŽ .see Section 2 . The low SANS group had a total

Ž . Ž .SANS score S.D. of 7.2 1.9 , with a range of4�10. The high SANS group had a total SANS

Ž . Ž .score S.D. of 13.5 2.6 , with a range of 10�18.A repeated measures ANOVA using

schizophrenic group’s Z scores was computedŽseparately for each tissue type gray and white

. Žmatter using the factors SANS group high or. Ž .low total SANS score and side right or left .

Gray matter volumes showed no significant dif-ferences between SANS groups. White mattervolumes were significantly different between

ŽSANS groups F�4.12; d.f.�1,29; P�0.052 forabsolute volumes; F�5.88; d.f.�1,29; P�0.022

.for relative volumes . The higher SANS scoregroup had reduced white matter compared with

Ž .the lower SANS group see Fig. 2 .The SANS group by side interaction was not

significant. Significant correlations were foundbetween Z-scores for left white matter and SANS

Žscores of the combined schizophrenic group r��0.50, P�0.005 abs. vol.; r��0.49, P�0.005

.rel. vol. . Significant correlations were also found


between Z-scores for total prefrontal volumeŽ .gray and white matter combined and total SANS

Žscores r��0.43, P�0.019 abs. vol.; r��0.38,.P�0.04 rel. vol. .

4. Discussion

The present study used high resolution MRIin conjunction with semi-automated image-processing procedures to measure whole pre-frontal cortical gray and prefrontal white mattervolume in schizophrenic and control subjects. Nosignificant differences were found between thetwo groups in either right or left gray mattervolume; however, right white matter volume wassignificantly reduced in the schizophrenic groupwhen compared with control subjects. These re-

Ž .sults are similar to those of Breier et al. 1992 ,whose methodology has comparable image reso-lution to that used in the present study. TheBreier et al. study also did not find gray mattervolume reductions in schizophrenic subjects, butdid report white matter volume reduction on both

Ž .sides of the brain. Buchanan et al. 1993 alsoreported white matter abnormalities in schizo-phrenic subjects.

White matter abnormalities were not found inour previous sample of positive symptomschizophrenic subjects. The different findings arelikely to be a result of the different symptom

Ž .profiles of the previous positive symptom andŽ .current negative symptom groups. In the current

study, 11 of the 17 patients had predominatelymixed symptoms, four had mainly positive symp-toms, and two had mainly negative symptoms. Inthe previous study, symptom profiles were verydifferent. Eleven of the 14 patients were assessedas having mainly positive symptoms, three patientswere characterized as having mixed symptoms,and none of the patients had predominately nega-

Ž .tive symptoms Wible et al., 1995 .Schizophrenic subjects from our previous and

current studies were combined and split into twogroups based on SANS total score. This combinedanalysis showed that the Z-scores for bilateralwhite matter volumes were significantly smaller inschizophrenic patients from the higher SANS

Ž .group see Fig. 2 . In other words, the higher theSANS score, the smaller the prefrontal whitematter volumes. Although much of the method-ology stayed constant between the current andprevious studies, caution must be taken in inter-preting results from combined studies that wereperformed at different times with differing

Ž .methodologies. Sanfilipo et al. 2000 also foundan association between white matter volume andnegative symptoms in schizophrenic subjects. Theyreported that the white matter reduction wasmost severe in the orbitofrontal region. Gur et al.Ž .2000 reported an association, in womenschizophrenic subjects only, between decreased

Ž .orbital gray matter volumes and negative symp-toms. In the current sample, we also found asignificant correlation between total SANS scoresand left frontal gray matter volume inschizophrenic subjects. Together these findingsuggest a relationship between prefrontal abnor-malities and negative symptoms.

The lack of gray matter or total volume find-ings is also in agreement with several other stud-ies that have reported no volumetric differencesin this area between schizophrenic and control

Ž .subjects see Table 1 . However, a reduction inwhite matter volume is likely to signify degenera-tion or cell death either in the frontal lobe or inregions that project to the frontal lobe. Thus, thisfinding of white matter reduction is not inconsis-tent with or contradictory to the reports of graymatter volume reductions that have been re-

Ž .ported in several studies see Table 1 . A whitematter volume reduction followed by changes ingray matter would suggest different primarypathological loci or processes than would either afinding of only gray matter loss or a finding ofboth gray and white matter loss combined. Theseissues need to be resolved in future research.

Temporal lobe pathology has been demon-strated in schizophrenic subjects using both MRI

Žand post-mortem histological studies for reviews,see Shenton et al., 1997; Wible et al., 1997; Mc-

.Carley et al., 1999 . Correlations were foundbetween volumes of right hippocampal and rightprefrontal gray matter volumes in schizophrenic,but not control subjects. These findings are again

Ž .similar to those of the Breier et al. 1992 study,


which found a significant correlation between theright hippocampal�amygdala complex and rightprefrontal white matter in schizophrenic subjects.The previous study from our laboratory found arelationship between anterior portions of the hip-pocampal�amygdala complex, parahippocampalgyrus, and superior temporal gyrus and prefrontalwhite and gray volume on the left side inschizophrenic subjects. Again, the differences incorrelations may be due to the different symptomprofiles of the previous and current patient groups.

The volume correlations found between tem-poral and prefrontal regions in schizophrenicpatients, but not control subjects, may indicatevolume reductions in tightly anatomically andfunctionally linked temporal�prefrontal regionssuch as hippocampal, superior temporal, cingu-late, orbital and inferior frontal regions. A de-tailed discussion of these ideas and the neuroana-tomical relationships can be found in Wible et al.Ž .1997 .

As in the previous study, here we hypothesizethat a use-dependent and�or developmentalpathological process that affects temporal lobestructures may also be affecting prefrontal corti-cal areas in a parallel manner, resulting instronger than normal relationships between

Ž .volumes in these areas Wible et al., 1997 .The lack of detection of gray matter volumetric

abnormalities in the current study should be in-terpreted with caution in light of the sensitivity ofMR findings. Abnormalities in cellular orienta-tion, connectivity, receptor distribution and sensi-tivity, and neurotransmitter distribution, amongother factors, are not detectable by MRI and

Žhave been previously reported Benes et al., 1986,.1991 . However, a histological study reporting

abnormalities in prefrontal areas did not find asignificant difference between schizophrenic andcontrol subjects in the cortical thickness of area 9of the prefrontal cortex because the differenceswere not large enough to reach significanceŽ .Selemon et al., 1995 .

The results of this study point to abnormaltemporal�prefrontal pathways, a finding for whichthere is converging evidence from many studies.The findings also suggest that there may be dif-

ferences in brain pathology or primary brainpathology in accordance with specific schizo-phrenic symptoms, and that negative symptomsmay be associated with prefrontal abnormalities.

Acknowledgements

This research was supported by the NationalInstitute of Mental Health through a National

Ž .Research Service Award MH 16259 JA , a K02Ž .award, MH 01110 MES , and MH 40799 and

Ž .MH 52807 RWM and Department of VeteransŽ .Affairs Merit MES, RWM and Middleton

Ž .RWM awards.

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