BRITISH JOURNAL OF PSYCHIATRY 2001), 178, 337^343

Schizophrenia and the frontal lobes from three centres Oxford, Belfast and Wickford in Essex)) in the UK and then Post-mortem stereological study of tissue volume assigned a randomised code by a third party so that measurements could be made blind to gender, diagnosis and age. Brains were J.J.ROBINHIGHLEY,MARYA.WALKER,MARGARETM.ESIRI, ROBIN HIGHLEY, MARY A. WALKER, MARGARET M. ESIRI, stored in formalin for an average of 3.25 BRENDAN McMcDONALD,DONALD, PAUL J. HARRISONand TIMOTHY J. CROW years prior to use in the study. It has been observed that any volume alterations related to fixation stabilise after a maxi- mum of 3 weeks Quester & SchroSchroder,È der, 1997), and therefore, as all brains were fixed in excess of this duration, it can be as- Background It has been suggested Evidence from both functional and sumed that they had reached their stable thatthatthere there is frontallobe involvement neuropathological studies suggests that the state.state. frontal lobes are affected in schizophrenia The brains were screened to ensure that in schizophrenia, and thatitthat it may be Goldman-Rakic & Selemon, 1997), raising they were free of neuropathological disease. lateralised and gender-specific. the issue of the potential for differences in Brains from patients who had undergone the volume of frontal lobe tissue between leucotomy were excluded. Patients' clinical Aims ToclarifyTo clarify the structure ofofthe the individuals with and without schizo- notes were assessed by a psychiatrist T.J.C. frontallobesinfrontallobes in schizophrenia in a post- phrenia. There is some evidence in the or Steven J. Cooper see Acknowledgements)) mortem series. existing literature for either a reduction in to ensure that diagnoses conformed to frontal lobe grey matter volume or a global DSM±IV American Psychiatric Association, MethodMethod The volume of white matter cortical reduction that is more marked in 1994) criteria for schizophrenia or schizo- and cortical components oftheof the frontal the frontal lobes Breier et aletal, 1992). There affective disorder. The control subjects' lobes was measured in brains of controls is additional evidence for lateralised altera- clinical notes were screened to ensure that they were free of psychopathology. and patients with schizophrenia using tions in the frontal lobe volume in schizo- phrenia Bilder et aletal, 1994). Early studies The mean age, cerebrum weight and planimetry and the Cavalieriprinciple. defined the posterior limit of the frontal post-mortem delay, as well as hospital of The components measured were: lobes with some arbitrary landmark e.g. origin, cause of death and number of cases superior frontal gyrus, middle frontal the genu of the corpus callosum), as in the different groups, are given in Table 1. gyrus, a composite of inferior frontal opposed to the central sulcus, which is ana- As can be seen from Table 1, the females tomically a more valid boundary. A pre- were significantly older than the males. gyrus and orbito-frontal cortex, as well as vious study of the present brain collection For this reason, age was entered into all total frontallobefrontal lobe cortex and white matter. HighleyHighley et aletal, 1998,1998aa) suggests that taking ANOVAs as a covariate. In addition, the anterior cingulate gyrus proper account of the central sulcus may was measured. be important. In that study, the length from the frontal pole to the central sulcus was MethodsMethods ResultsResults No diagnosis, gender, measured dorsally over the external surface The frontal lobes were defined as all cortex diagnosisdiagnosis66side, diagnosis66gender ororgender of both frontal lobes on post-mortem and white matter anterior to the central brains and a striking gender66diagnosisdiagnosis diagnosisdiagnosis66gendergender66side interactions sulcus. The basal ganglia, insula, ventricles interaction was found see Discussion). and internal capsule were not included. were observedinobservedinthe the volume of anyof The present study was performed to eluci- All brains were stripped of the leptome- the components, the grey matter as a date the nature of volumetric differences ninges and bisected in the median sagittal whole or the white matter.No evidence if present) in the brain in schizophrenia, plane. The temporal and occipital lobes for volumetric inter-group differences when the frontal lobes are defined in a were dissected away by sectioning the white non-arbitrary manner. The following struc- matter running between the temporal and was found for the anterior cingulate tures were measured: the pre-central gyrus, frontal lobes and insula, and a cut through gyrus.gyrus. the superior frontal gyrus, the middle fron- the parietal lobes. tal gyrus, a composite of the inferior frontal Either side of the central sulcus, the pre- Conclusions Such structural gyrus and orbito-frontal cortex, the total and post-central gyri were painted with abnormalities as are presentinthepresent in the frontal frontal lobe cortex and white matter. In permanent ink of different colours. The lobes are more subtle than addition, the anterior cingulate volume frontal lobes were then sectioned into straightforward alterationsintissue was assessed. serial, parallel coronal slices using 5-mm guides. After slicing, the slices were reas- volume; theymayinclude changesin shape sembled into a stack excluding the first and the pattern of gyral folding. METHOD and last slices), the length of which was measured and divided by the number of Declaration of interest This work Tissue slices, to generate the mean slice thickness. was supported byThe Medical Research Brains were fixed by suspension from the For all further measures, allall slices including Council and The WellcomeTrust. basilar artery in 10% formalin, collected first and last) were included.

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TaTable b l e 1 The mean s.d.) age, cerebrum weight and post-mortem delay, as well as hospital of origin and and cause of the hemisphere, it lies superior to the of death of cases cingulate. Anteriorly it wraps around the front of the cingulate to meet up with the orbito-frontal cortex. The superior ControlSchizophrenia frontal gyrus lies superior to the middle FemaleMale FemaleMale frontal gyrus, separated from it by the superior frontal sulcus. Number of cases 13 15 919 155 TheThe middle frontal gyrus lies between Age11,,years years74.6 13.3) 74.6 13.3)67.2 14.5)73.3 17.6)60.9 15.3) the superior and inferior frontal gyri and Cerebrum weight22 0.96 0.14) 0.14)0.96 1.12 0.09) 0.09)1.12 0.86 0.15) 0.15)0.86 1.15 0.13) is bounded by the superior and inferior brain less brain-stem, kg) frontal sulci. Posteriorly it abuts the pre- DeathDeathtopost-mortemdelay to post-mortem delay33,, 43.3 26.9) 26.9)43.3 42.6 28.5) 28.5)42.6 43.44 38.1)48.2 33.1) central gyrus, and is separated from it by hourshours the pre-central sulcus. Duration in fixative44,,years years2.54 1.33)2.54 1.33) 2.13 1.30) 1.30)2.13 5.22 1.86) 1.86)5.22 3.79 2.12) 2.12)3.79 TheThe infero-orbital cortex is a composite of the inferior frontal gyrus and the orbito- HospitaloforiginHospital of origin55,, 0/10/30/13/2 6/1/26/1/2 5/5/55/5/5 frontal cortex. These two were com- Belfast/Oxford/Runwell pounded because it proved to be impossible Cause of death66,, 8/1/38/1/3 12/3/012/3/0 2/3/22/3/2 5/4/55/4/5 to reliably separate one from the other. The cardiac/respiratory/other inferior frontal gyrus is inferior to the 1. Femalessignificantly older than males:by ANOVA, FF 1,48)ˆ5.43,5.43, PPˆ0.024. middle frontal gyrus, separated from it by 2. Femalessignificantly lighter than males:by ANCOVAwith age ascovariate, FF 1,46) 1,46)ˆ30.24,30.24, PP550.0005.0.0005. the inferior frontal sulcus. Medially, the 3. No inter-group differences: all FF 1,46) 1,46)440.10,0.10, PP440.7.0.7. 4.4.Controls Controlssignificantly significantly shorter shorter than than patients patients FF 1,47) 1,47)ˆ20.70,20.70, PP550.0005); trend to femaleslonger than males orbito-frontal cortex is bounded by that FF 1,47) 1,47)ˆ3.73,3.73, PPˆ0.059).0.059). portion of the anterior cingulate that lies 5. No control brainswerebrains were collected collected at at Belfast,sothere Belfast, so there were were significant significant group group differencesin differences hospitalin hospital of origin: of origin: underneath the rostrum of the corpus ww22ˆ25.27,d.f.ˆ6,6, PP550.0005. Runwell Hospital located at Wickford in Essex. 6. No inter-group differences: ww22ˆ11.23, d.f.d.f.11.23, ˆ6,6, PPˆ0.081.0.081. callosum and anterior to the genu. All grey matter on the inferior surface of the frontal lobes was included in this measure. The posterior aspect of each slice was Between the most anterior extent of the TheThe frontal pole was defined as all the patted dry of excess moisture and photo- central sulcus and the level at which the grey matter on the most anterior one or graphed using colour slide film, with a ruler frontal and temporal lobes are no longer two slices in the situation where the differ- in the field of view, ensuring that the planes connected, the inferior boundary of the ent gyri were indistinguishable. The sole of the camera lens and the brain slice were white matter was defined by a straight line use of this measure was to be summated parallel. These photographs were then from the superior insular circular sulcus to with the other grey matter measures to give projected, in a random position, at an the most supero-lateral point of the lateral the total frontal lobe cortical volume. approximate magnification of661.7onto a1.7ontoa ventricles. Anterior to the join between TheThe anterior cingulate gyrus lies super-liessuper- counting grid. The counting grid consisted frontal and temporal lobes, all white matter ior to the corpus callosum and curves of a series of crosses in a regular, uniform on the slice was counted, including white anteriorly and inferiorly around the genu. square array. The density of crosses was matter interposed between the basal ganglia The posterior boundary of the anterior cin- such that one cross represented an area of and the orbito-frontal cortex. The internal gulate was at the level one-fifth along the 2cm22 on the counting grid. A subset of capsule was not included. maximal anterior±posterior length of the these crosses was circled such that one The frontal lobe cortex was subdivided corpus callosum. The cingulate was identi- circled cross represented 4 cm22 on theonthe into the following regions: primary motor fied superior, anterior and inferior to the counting grid. The total number of crosses cortex/pre-central gyrus; infero-orbital corpus callosum. circled or otherwise) falling on each cortex; middle frontal gyrus; superior cortical structure of interest was counted frontal gyrus; and frontal pole. In addition, for each slice and then summated. The the cortex of the anterior cingulate gyrus RESULTSRESULTS number of circled crosses falling on white was counted. In six cases the anterior matter were counted and again summated. cingulate gyrus had been damaged during Analysis of measurement protocol From these counts, the spacing of the bisection of the hemispheres, and in these The observed coefficients of error OCE) grid, the magnification of the frontal lobe cases the measure was excluded. The for estimates of volume were calculated as images and the mean slice thickness were anterior cingulate was excluded from the described by Gundersen & Jensen 1987). calculated estimates of the volumes of the total frontal cortical volume. The basal The mean value of OCE was calculated regions of interest, by application of the ganglia, thalamus and other subcortical for each measure for each group female Cavalieri principle Gundersen et aletal,, grey matter structures were not counted. control, male control, female schizophrenia 1988).1988). The subdivisions are depicted in Fig. 1. and male schizophrenia). The highest On slices on which the central sulcus TheThe motor cortex was defined as the mean value of OCE for any grey matter was visible, a line from the central sulcus pre-central gyrus. component measure for any group was to the most supero-lateral point of the TheThe superior frontal gyrus abuts theabutsthe 0.087. For the total grey and white lateral ventricles defined the inferior pre-central gyrus, separated from it by the matter volumes, the maximum mean OCE boundary of the frontal lobe white matter. pre-central sulcus. On the medial surface values observed were 0.033 and 0.055,

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Comparison with previous studies The volume of total frontal lobes has been measured in a number of other studies, the most comparable being those of Pakkenberg 1993) and Pakkenberg & Gundersen 1997). In the former, the total volume left+right) of cortex in the frontal lobe was measured in males both with and without schizophrenia. Although not explicitly stated, it appears that this mea- sure included the cingulate. For the control males, the mean volume 211.6 cm33) was)was significantly larger ttˆ3.400, d.f.ˆ29,29, PPˆ0.002) than the equivalent volume in the present study 174.4 cm33). For the males with schizophrenia there was no significant difference ttˆ0.928, d.f.ˆ18,18, PPˆ0.366)0.366) between the measures of Pakkenberg 182.2 cm182.2cm33) and the present study 195.8 cm195.8cm33). Pakkenberg & Gundersen also measured the same volume in males unaffected by schizophrenia, and again recorded a significantly higher volume 213 cm213cm33) than the present study ttˆ3.585,3.585, d.f.d.f.ˆ75,75, PPˆ0.0006). These workers also measured the volumes of females without schizophrenia, finding the mean volume to be 184 cmcmbe184 33, which did not differ signifi- cantly cantlyttˆ1.195, d.f.1.195,d.f.ˆ41,41, PPˆ0.239) from the equivalent volume in the present study 169.4 cm169.4cm33). The reason for the smaller values in the present study for control males is unclear, but there may possibly be slight differences in the working definition of the frontal lobes. However, given that two out of three of the groups for which a meaningful comparison can be made show no such difference, it can be concluded that the measures achieved in the present study reasonably estimate the volumes of frontal lobe structures.

Effects of diagnosis and gender Fig. 11Fig. The frontal lobe structures as defined in this study: PCG, pre-central gyrus; ACG, anterior cingulate The mean values of each measure are gyrus; SFG, superior frontal gyrus; MFG, middle frontal gyrus; IOC, infero-orbital cortex aa most posterior to shown in Table 2. For each frontal lobe ee most anterior). grey matter component pre-central gyrus, superior frontal gyrus, middle frontal respectively. These values are all accepta- minimum of 91.0% of the observed relative gyrus, infero-orbital cortex), an ANCOVA ble, being less than the target average variance for the grey matter component was performed with diagnosis and gender value of 0.1 that was chosen when measures. For the total grey matter and as between-subject factors, side as a with- planning theinvestigation. white matter volumes, true inter-individual in-subject factor and age as a covariate. From the mean values of OCE, one can variation accounted for a minimum of The main effects of gender and diagnosis estimate the percentage of observed relative 97.6% of the observed relative variance were tested for, as were diagnosis66gender,gender, variance of each measure for each subject for the different comparison groups. diagnosisdiagnosis66side and diagnosis66gendergender66 group accounted for by true inter- For the cingulate gyrus, the largest side interactions. The results of these individual variance, as opposed to inaccu- mean OCE was 0.079. True inter- analyses are given in Table 3. For analysis racy in the stereological volume estimate. individual variation accounted for a of the frontal cortical components, aa waswas For each comparison group, true inter- minimum of 90.1% of the observed relative set to 0.0125 prior to the analyses individual variation accounted for a variance for any group. because four such regions were studied.

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Ta b l e 2 The mean s.d.) volume measures in cm33)foreachgroup the infero-orbital cortex. The gender effect reflected smaller volumes in the female Female Male brains compared with the male brains. The interaction corresponded to a smaller ControlPatient Control Patient volume in female patients and an elevated volume in male patients compared with Pre-central gyrusLeftgyrus Left 17.6 2.82) 2.82)17.6 18.2 2.71) 2.71)18.2 20.6 4.97) 4.97)20.6 20.1 5.13) 5.13)20.1 controls. However, given the large number Right17.5 4.87) 18.1 4.14) 4.14)18.1 18.1 4.02) 19.5 5.09) 5.09)19.5 of effects examined for, this is likely to be Superior frontal gyrusLeftgyrus Left 18.8 3.78) 3.78)18.8 17.6 3.93) 3.93)17.6 19.0 3.99) 3.99)19.0 19.9 3.83) a chance occurrence. Right20.4 4.62)17.8 4.95)19.4 5.19)21.6 4.44) Middle frontal gyrusLeftgyrus Left 12.2 2.16) 2.16)12.2 11.9 3.30) 3.30)11.9 12.1 3.71) 3.71)12.1 13.8 3.51) 3.51)13.8 Relationship between measures Right11.7 3.46) 12.1 2.89) 2.89)12.1 12.3 3.38) 3.38)12.3 13.2 3.64) 3.64)13.2 obtained from this and other Infero-orbital cortexLeft 20.9 4.31) 4.31)20.9 18.7 6.99) 6.99)18.7 22.6 5.28) 5.28)22.6 26.3 6.68) 6.68)26.3 studies Right21.9 5.52) 20.3 4.97) 4.97)20.3 21.7 6.78) 6.78)21.7 25.7 5.42) 5.42)25.7 This study was designed in part to investi- Total grey matter LeftLeft 74.5 11.2) 11.2)74.5 69.9 11.9) 11.9)69.9 79.9 15.7) 15.7)79.9 86.0 11.2) 11.2)86.0 gate whether a gender66diagnosis interac- tion in the asymmetry of the length of the Right76.0 14.1)72.1 11.1)76.6 15.3)84.7 13.5) frontal lobes over their superior surface as White matter Left 67.7 24.9) 24.9)67.7 68.0 18.2) 18.2)68.0 72.7 31.4)88.4 19.1) found in a prior report Highley et aletal,, Right 66.1 22.4) 22.4)66.1 63.1 17.6)71.3 32.1) 86.3 18.7) 18.7)86.3 19981998aa) was due to alterations in the volume Cingulate gyrusLeftgyrus Left 9.55 2.27) 2.27)9.55 8.80 3.58) 3.58)8.80 9.32 2.39) 2.39)9.32 10.4 1.86) of the superior frontal gyrus. To investigate Right 8.97 2.44) 2.44)8.97 8.51 2.08) 2.08)8.51 8.60 2.06) 2.06)8.60 9.92 1.45) the relationship between the two measures, the correlations between the superior frontal length and the volume of the TaTable b l e 3 Results of the ANCOVAs of frontal lobe volume data superior frontal gyrus as measures were assessed. As it was also feasible that the DiagnosisGender Diagnosis 66 Diagnosis66 Gender66 middle frontal gyrus may be related to this gender side side66diagnosis length measure, the correlation with this volume was also assessed. The results of Pre-centralPre-central FF 1,47) 1,47)ˆ0.09 FF 1,47) 1,47)ˆ1.13 FF 1,47)ˆ0.05 FF 1,48)ˆ0.48 FF 1,48)ˆ0.500.50 these tests are given in Table 4. gyrus PPˆ0.766 PPˆ0.293 PPˆ0.828 PPˆ0.491 PPˆ0.485 All of these correlations were signifi- Superior frontal FF 1,47)ˆ0.11 FF 1,47) 1,47)ˆ0.440.44 FF 1,47)ˆ2.12 FF 1,48)550.005 FF 1,48) 1,48)ˆ1.62 cant but modest: the greatest correlation gyrus PPˆ0.746 PPˆ0.5120.512 PPˆ0.152 PPˆ0.989 PPˆ0.210 coefficient is rrˆ0.4743 for the left middle Middle frontal FF 1,47) 1,47)ˆ0.42 FF 1,47) 1,47)ˆ0.320.32 FF 1,47)ˆ0.39 FF 1,48)550.005 FF 1,48)ˆ0.77 frontal gyrus), suggesting that variations gyrus PPˆ0.519 PPˆ0.5720.572 PPˆ0.534 PPˆ0.985 PPˆ0.3840.384 in the left middle frontal gyrus volume Infero-orbital FF 1,47)ˆ0.25 FF 1,47)ˆ4.034.03 FF 1,47)ˆ3.413.41 FF 1,48) 1,48)ˆ0.08 FF 1,48)550.005 can account for only 22.5% of the variance of the length measure. All other correlation cortexcortex PPˆ0.618 PPˆ0.0500.050 PPˆ0.071 PPˆ0.7770.777 PPˆ0.956 coefficients were smaller than this. Total grey FF 1,47)ˆ0.04 FF 1,47) 1,47)ˆ3.37 FF 1,47)ˆ2.232.23 FF 1,48)ˆ0.260.26 FF 1,48)ˆ0.06 mattermatter PPˆ0.8400.840 PPˆ0.073 PPˆ0.142 PPˆ0.6100.610 PPˆ0.815 Potential artefacts White matter FF 1,47)ˆ0.620.62 FF 1,47)ˆ1.551.55 FF 1,47)ˆ1.211.21 FF 1,48)ˆ0.390.39 FF 1,48)ˆ0.150.15 It may be argued that some aspects of brain PPˆ0.4360.436 PPˆ0.219 PPˆ0.278 PPˆ0.5360.536 PPˆ0.6970.697 extraction and fixation in different hospi- Cingulate cortex FF 1,41)ˆ0.06 FF 1,41)ˆ0.130.13 FF 1,41)ˆ1.85 FF 1,42)ˆ0.150.15 FF 1,42) 1,42)550.005 tals may have differentially affected the PPˆ0.812 PPˆ0.721 PPˆ0.1810.181 PPˆ0.700 PPˆ0.9830.983 tissue studied in this paper. This was analysed for both grey and white matter using the data from the males with schizo- TaTable b l e 4 Correlation between the superior frontal length and the volume of the phrenia five cases came from each of the ipsilateral superior and middle frontal gyri three centres). Two repeated-measures ANOVAs were performed to investigate Superior frontal gyrusvolume MiddleMiddle frontal frontal gyrusvolume gyrusvolume the effect of hospital of origin on the total grey and white matter volumes. There was Left length rrˆ0.3297, d.f.ˆ47, PPˆ0.0210.021 rrˆ0.4743, d.f.d.f.0.4743, ˆ47, PPˆ0.001 no effect of origin on either the total grey Right length rrˆ0.3130, d.f.ˆ47,47, PPˆ0.0290.029 rrˆ0.3026, d.f.d.f.0.3026, ˆ47,47, PPˆ0.0350.035 volume volumeFF2,12)2,12)ˆ0.88,0.88, PPˆ0.440) or the white matter volume FF2,12)2,12)ˆ0.16,0.16, PPˆ0.853).0.853). GoldsteinGoldstein et aletal 1999) assessed the The frontal lobe total grey and white These analyses yielded no significant volumes of grey matter components while matter and cingulate cortex were analysed effects. There were non-significant trends controlling for overall cerebrum volume. in a similar manner but with aa set tosetto towards a gender effect and a diagnosis66 The inclusion of cerebrum weight as well 0.05.0.05. gender interaction effect on the volume of as age as a covariate in the ANCOVA

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Ta b l e 55Tab Summary of results of this and previous studies

Pakkenberg 1993)Baare ¨ et aletal 1999) 1999)Buchanan et aletal Goldstein et aletal Crespo-Facorro Present study 1998) 1998) 1999) 1999) et aletal 2000) 2000)

Superior frontal gyrus0gyrus 000000000 Middle frontal gyrus0gyrus 000LLefteft;; 000 0 Inferior frontal gyrus11 Bilateral;; 000 0 00 00 Orbito-frontal cortex11 } 0R0 Rightight;; 00 }

Total grey matter 000 0000000 Frontal white matter ;; 00

1.Orbito-frontal1. Orbito-frontal and inferior frontal cortices are merged in the current study and in the study of of Baare Baare¨ et al.. 0, no significant difference in volume between patients and comparison subjects.

analysis of data in this study did not alter corpus callosum as the boundary between GoldsteinGoldstein et aletal, 1999; Crespo-Facorro etet the outcome of the analyses. the pre-frontal and pre-motor cortices. alal, 2000) together with the present study, The possible effect of death to fixation However, there is evidence for alterations it would appear that the frontal lobe grey delay and duration in fixative was investi- in callosal anatomy in schizophrenia matter volumes are unaltered in schizo- gated by repeating all the ANCOVAs for WoodruffWoodruff et aletal, 1995; Highley et aletal,,1999 1999aa).). phrenia. The view that the structural cortical components, total grey and white Since the current study was com- changes in schizophrenia are selective to matter and anterior cingulate, with fixation menced, four magnetic resonance imaging the frontal lobes as suggested by Shelton delay and duration as covariates. These MRI) studies have examined frontal lobe et aletal 1988) is unsupported. By contrast, analyses revealed no effect of either fixation cortical volumes in schizophrenia using as noted by Wible et aletal 1995), the litera- delay alldelayall770.2270.22755zz551.869, all1.869,all PP550.069)0.069) either the pre-central or central sulci as ture contains many reports of reductions or duration in fixative all771.6831.68355zz the boundary of frontal lobe components in the volume of temporal lobe structures 550.511, all0.511,all PP550.100). The outcomes of BuchananBuchanan et aletal, 1998; Baare et aletal, 1999;,1999; that are either selective to or greater on the analyses of the effects of diagnosis and GoldsteinGoldstein et aletal, 1999; Crespo-Facorro etet the left Highley et aletal, 1999,1999bb; McDonald gender were not altered. alal, 2000). The findings of these studies, et aletal, 2000). In addition, many studies and the post- mortem study mentioned observe a non-lateralised reduction in the aboveabovePakkenberg,Pakkenberg, 1993), are summarised volumes of temporal lobe structures DISCUSSION in Table 5. In addition, Szeszko et aletal 1999)1999) ZipurskyZipursky et aletal, 1994). Other temporal lobe have performed an MRI analysis of frontal pathology includes a relatively greater This study finds no evidence for any lobe components with measures including enlargement of the temporal horn than the alteration, lateralised or otherwise, in the white as well as grey matter. rest of the lateral ventricle Crow et aletal,, volume of the cortex or white matter of As can be seen from Table 5, the 1989),1989),andand shortening of the temporal the frontal lobe or of the anterior cingu- majority of measures made in these studies lobeslobesHighleyHighley et aletal, 1998,1998bb). Such findings late gyrus.lategyrus. find no effect of schizophrenia. Those raise the possibility of a qualitative differ- effects that are found are inconsistent enceencebetweenbetween frontal and temporal lobes between studies. For example, Szeszko as the site of a pathophysiology of schizo- Previous studies of the frontal lobes et aletal's measure of orbito-frontal tissue phrenia.phrenia. When this study was commenced, only one which included underlying white matter) For the anterior cingulate gyrus, consis- study assessing any aspect of frontal lobe found a right-sided increase in male but tent with the current report, three MRI size had used the anatomically correct not female patients with schizophrenia. studies have found no alteration in the central or pre-central sulcus as the bound- This was not replicated in any other study. volume of this structure Noga et aletal,, aryaryPakkenberg,Pakkenberg, 1993). With this exception, The reduction in prefrontal white 1995; Woodruff et aletal, 1997; Szeszko et aletal,, prior studies used arbitrary landmarks to matter volume excluding white matter 1999). Three studies that report differences select coronal slices to define the posterior underlying the pre-central sulcus) reported lack a consensus as to what the differences boundary, a procedure that is unsatisfac- by Buchanan et aletal 1998) was not confirmed are. Albanese et aletal 1995) measured the tory on two counts: first, if the position of in the present study which included all weight and surface area of the anterior the central sulcus the true boundary of white matter). No other study has cingulate from dissected post-mortem the frontal lobes) should alter in schizo- measured white matter using appropriate brain. They found controls to show a phrenia, such that more or less cortex lies landmarks, leaving this disagreement right-greater-than-left asymmetry, whereas within the frontal lobes, this will not be de- unresolved.unresolved. patients showed the opposite or absence tected; and second, if the position of a land- of asymmetry. Examination of their data mark used to delineate the frontal lobe reveals this to be largely due to right-sided boundary is altered in schizophrenia, this Is the primary focus reductions in anterior cingulate volume may adversely affect the volumes estimates. in the temporal lobes? and surface area. In contrast, Goldstein Thus, for example, both Bilder et aletal 1994)1994) Taking these studies Pakkenberg, 1993; et aletal 1999) claim a reduction in total and BreierandBreier et aletal 1992) used the genu of the BuchananBuchanan et aletal, 1998; Baare et aletal, 1999;,1999; presumably left+right) anterior cingulate

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volume. Finally, Hirayasu et aletal 1999)1999) describe a non-significant left-sided volume CLINICAL IMPLICATIONS reduction in that portion of the cingulate that lies inferior to the corpus callosum, a && The volumesof the frontal lobesare unchanged in schizophrenia, in contrastwith measure in which Goldstein et aletal 1999)1999) decreased volumes and altered asymmetries in the temporal lobes. found no change. && Thiscombination of findingsconstrainstheoriesof the origin of the structural brain changesin schizophrenia.

&& Schizophrenia cannot be considered as a simple disorder of the frontal lobes. Surface asymmetries and sulco-gyral structure LIMITATIONS

A previous study on this set of brains && Although large for a post-mortem study, the sample size does not exclude small HighleyHighley et aletal, 1998,1998aa) reported a striking differencesin frontal lobe volume in schizophrenia. and unexpected gender66diagnosis inter- action in the length from the frontal pole && There may be alterationsin other morphological aspectsof the frontal lobes e.g. to the central sulcus when measured over sulco-gyral structure and cellular composition). the superior surface of the brain. Female controls had a left-greater-than-right && The study was limited to frontal lobe structure. asymmetry and male controls had a right- greater-than-left asymmetry; the pattern was reversed in schizophrenia. No signifi- cant effect was apparent when the tape measure was passed around the lateral J. ROBIN HIGHLEY, DPhil, MARYA.WALKER, MARGARET M. ESIRI, FRCPath, BRENDAN McDONALD, MRCPath, Schizophrenia Research Group, Department of Clinical Neurology 8Neuropathology), Radcliffe aspect of the brain, suggesting a regional Infirmary,Oxford; PAUL J. HARRISON, DM,DM,University University Department of Psychiatry,Neurosciences Building, specificity. We predicted that this asymme- Warneford Hospital,Oxford;TIMOTHY J.CROW,FRCPsych, POWIC,University Department of Psychiatry, try would reflect a gender66diagnosisdiagnosis66sideside Warneford Hospital,Oxford,UK interaction in the volume of the superior temporal lobe. No such volume changes CorrespCorrespondence:Timothyondence:Timothy J.Crow,POWIC,University Department of PsychPsychiatry,iatry, were observed. Warneford Hospital,Oxford OX3 7JX,UK.Tel: +44 1865 223909; Fax: +44 1865 244990; The minimal relationship between the e-mail: tim.crow@@psychiatry.oxford.ac.uk frontal lobe length measures of our prior 8First received17received 17 January 2000, final revision19revision 19 September 2000, 2000, accepted19 accepted 19 September September 2000) 2000) study and the volume measures of the present study may explain the failure to demonstrate the hypothesised gender66 diagnosisdiagnosis66side interaction in superior ACKNOWLEDGEMENTS resonance imaging study of limbic, prefrontal cortex, and caudate structures. Archives of General Psychiatry,, frontal gyrus volume: some aspect of 49, 921^926.,921^926. frontal lobe anatomy other than volume The authors would like to thank Dr Steven J.Cooper andDrBrianM.Herronfortheirassistancewithand Dr Brian M. Herron for their assistance with Buchanan, R.W.,Vladar, K., Barta, P. E., et aletal 19 9 8) must be responsible for the interaction acquiring tissue and analysing clinical notes. This Structural evaluation of the prefrontal cortex in effect on the length measure. An obvious project was funded by an MRC project grant to schizophrenia. American Journal of Psychiatry,, 155155,1049^ 1055.1055. alternative is the shape and sulco-gyral M.M.E. and T.J.C. and a WellcomeTrust project grant structure of the lobe. Gyral folding can to M.M.E. and P.J.H. Crespo-Facorro, B., Kim, J.-J., Andreasen, N. C., be viewed as an index of cortico-cortical et aletal 2000)2000) Regional frontal abnormalities in schizophrenia: a quantitative gray matter volume and connectivity Griffin, 1994; Van Essen, REFERENCES corticalsurfacesizestudy.cortical surface size study. Biological Psychiatry,, 48,, 1997). There is evidence for alterations 110^119.110^119.

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