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Ventricular enlargement in schizophrenia: a primary change in the temporal lobe?
Schizophrenia Research 62 (2003) 123 – 131 www.elsevier.com/locate/schres
Ventricular enlargement in schizophrenia: a primary change in the temporal lobe? Steven A. Chance *, Margaret M. Esiri, Timothy J. Crow University of Oxford, Oxford, UK Received 15 November 2001; accepted 21 June 2002
Abstract Background: The anatomical origin of the enlargement of the cerebral ventricles in schizophrenia is obscure. Methods: In this study, the volumes of the hemispheres and lateral ventricles were assessed in MRI scans of 43 formalin-fixed brains (23 from patients and 19 comparison subjects) using a spline ‘snake’ segmentation method. Results: A bilateral ventricular volume increase was found in schizophrenia. Whereas enlargement of the lateral ventricle (mean: 54%) as a whole was related to age of onset and was greater in females than in males, enlargement of the temporal horn (mean: 54%) was not strongly related to age of onset or sex. Lateral ventricle volume was negatively correlated with STG, fusiform and parahippocampal volume in schizophrenia. Hemispheric volumes were unchanged. Conclusions: The differing correlates of the components of ventricular enlargement suggest a degree of selectivity of the disease process with a focus in the temporal lobe. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Ventricles; Parahippocampal; Sex; Gyrus; Temporal
1. Introduction Of 43 MRI studies in which lateral ventricle size was measured in schizophrenia, 77% found enlargement as did 75% of the earlier CT studies (McCarley et al., 1999). A mean increase of 26% has been estimated in MRI studies (Wright et al., 2000). Yet, the meaning for the disease process remains obscure. Lack of bimodality in the distribution of ventricular size within the patient group (Vita et al., 2000) suggests a single disease entity. Absent periventricular
* Corresponding author. Schizophrenia Research Group, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK. Tel.: +44-1865-228424; fax: +44-1865-228496. E-mail address: [email protected] (S.A. Chance).
gliosis (Roberts et al., 1987; Bruton et al., 1990) and the presence of ventricular enlargement at the time of the first episode (DeLisi et al., 1991) are consistent with a neurodevelopmental (Weinberger, 1987; Crow et al., 1989) rather than a degenerative origin. Ventricular enlargement presumably reflects a change in brain structure. There are indications that brain structural change is localised—temporal lobe volume (Dauphinais et al., 1990) and length (Crow and Crow, 1996; Highley et al., 1998a) have been found reduced relative to the brain as a whole. It has been suggested that temporal horn enlargement in schizophrenia is due to a volume reduction of adjacent limbic structures (Brown et al., 1986), and several MRI studies have found enlarged temporal horns and smaller temporal limbic structures (Bogerts et al., 1990; Kawasaki et al., 1993; Shenton et al., 1992).
0920-9964/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0920-9964(02)00344-4
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However, only Shenton et al. found a negative correlation between left temporal horn and left parahippocampal gyrus volumes, whereas the other two studies found no correlation and interpreted this as evidence against a simple interaction between limbic tissue loss and temporal horn enlargement. No correlation was also found between amygdala volume and temporal horn volume in brains from the series reported in the present study (Chance et al., 2002). This stands in contrast to the negative correlations between amygdala volume and temporal horn volume reported for epilepsy (a neurodegenerative rather than neurodevelopmental process). There is a tendency for enlargement of the ventricle to be greater on the left side (e.g. Bruton et al., 1990, DeLisi et al., 1991; Narr et al., 2001) in addition to the tendency for more marked enlargement of the temporal horns. These trends converge in studies that have found the temporal horn in the left hemisphere to be particularly enlarged (Bogerts et al., 1985; Crow et al., 1989). That the brain changes in schizophrenia have a genetic component is suggested by similar findings, e.g. a reduction in cortical grey matter (Cannon et al., 1998) and enlarged ventricles (Lawrie et al., 1999) in the siblings of patients. However, the ventricles are also found to be larger in the ill members of pairs of twins discordant for suffering from schizophrenia (Reveley et al., 1982; Suddath et al., 1990). Ventricular enlargement, therefore, and the expression of illness are dependent on both genetic and nongenetic factors (Silverman et al., 1998; Cannon et al., 1989)— perhaps better interpreted as epigenetic factors. Gender is one modulator of phenotype. Sex differences are present in both the expression of illness (i.e. in age of onset of psychosis) and the extent of abnormality of brain structure (Nopoulos et al., 1997) as well as in cerebral asymmetry (Bear et al., 1986). In this study, MRI scans from a series of postmortem brains were used to assess gross volume of the cerebral hemispheres, lateral ventricles and temporal horns to examine the selectivity of the change in ventricular structure to the temporal horns. An MRI method was chosen because this noninvasive technique allows ventricle volume to be assessed without compromising the structural integrity of the walls of the ventricles that may be distorted by dissection or the introduction of a radio-opaque medium for visualisation.
2. Methods and materials 2.1. Tissue Postmortem brains were suspended by the basilar artery for fixation in 10% formalin. Subsequent to diagnostic and pathological assessment and selection for absence of morphological distortion, the series consisted of 43 brains (from 14 male and 9 female patients with schizophrenia, and a comparison group of 10 males and 10 females). Age at death (mean in females: 73.3 years, males: 63.8 years) was treated as a covariate in later statistical analyses. Subjects were selected after assessment of clinical notes by a psychiatrist (TJC or SJ Cooper). DSM IV criteria for schizophrenia and schizoaffective disorder (one patient) were used for the selection of cases of schizophrenia. Cases were collected with the cooperation of the coroner (medical examiner) or from hospital postmortem examinations. Consent was obtained according to prevailing procedures with consent from the next-of-kin where appropriate. Pathological assessment of tissue samples was carried out by a neuropathologist (MME or B McDonald) using the CERAD criteria. All brains were confirmed to be free from major neuropathology (including Alzheimer’s disease, Parkinson’s disease and cerebrovascular disease) and free from gross morphological distortion. The degree of neuroleptic medication received during life was assessed from case notes, and categorised as little, average or much, based on a clinician’s judgement of the available clinical records (Table 1). The variability of the information available precluded a more quantitative estimation. Other potentially confounding variables, including age of symptom onset, postmortem interval and fixation time, were noted for statistical analysis. 2.2. Method Each formalin-fixed brain was scanned in a container of 10% neutral buffered formalin in a 1.5 Tesla GE Signa Advantage scanner, yielding 1.5 mm contiguous, coronal slices. The proton density weighted scanning protocol was optimised for grey-white matter contrast in formalin fixed tissue (Blamire et al., 1996). The plane of scan acquisition was approxi-
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Table 1 Demographic variables and details of the brain collection (mean and S.D.) Variable
Comparison males (n=10)
Schizophrenic males (n=14)
Comparison females (n=10)
Schizophrenic females (n=9)
Age at onset in yearsa Duration of illness in yearsa Age at death in years Postmortem interval in hours Fixation period in monthsb
NA NA 69.4F7.2 48.5F32.1 34.4F15.0
28.7F7.8 30.8F15.5 59.7F13.9 42.8F32.1 47.0F22.9
NA NA 69.9F13.8 45F25.5 27.7F16.1
32.9F10.3 44.2F13.8 77.1F13.6 40.1F36.1 55.2F23.2
a b
Inaccurate information for one case. Inaccurate information for four cases.
mated as orthogonal to the mid-sagittal plane and fronto-occipital axis as determined on a sagittal scout scan. This allowed the free-floating brain to be aligned for volume measurements of structures such as brain hemispheres and ventricles. The segmentation program was developed in Oxford University based on a so-called snake contour model. This is a semiautomated outlining method that utilises modified B-spline curves that fit to edges detected in their vicinity (i.e. the cortical surface), guided by the user (Marais, 1998). The snake outline possesses intrinsic regularising properties, which enable it to provide a smooth approximation to a boundary in the presence of image noise with subvoxel accuracy. Because the method has a limited capacity to match high velocity curves, it does not follow the
Fig. 1. A single coronal MR image of a postmortem brain, showing the spline snake program in use. The dashed line represents the spline outline; square dots on the line are the user interface for snake manipulation.
cortical surface into narrow sulci. Volume estimates were obtained as the product of multiplying snake area by slice thickness (Fig. 1). For validation, 26 brains, randomly selected from this cohort, were segmented for hemisphere volume. Total volumes of the 52 segmented hemispheres (with ventricles subtracted) were compared with estimates derived by the Archimedes principle of water displacement. Brains were dissected after scanning, the hemispheres submerged (allowing air to escape from the ventricular system), and displaced water escaped into a measuring cylinder. Statistical comparison of the two methods gave an intraclass correlation of 0.98. To define the lateral ventricles, the neck of the interventricular foramina of Monroe was used as the cut off point between lateral and third ventricles. To define the temporal horn, the first slice anterior to the trigone was used, at which point the temporal horn is distinct from the body of the lateral ventricle (Fig. 2).
Fig. 2. The position of the ventricular trigone delineated the posterior boundary of the temporal horn.
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Due to the small size of the temporal horn and its arbitrary posterior boundary, an attempt was made to limit the error due to anomalous scan alignment of the free-floating brains. Three scans, which had an angle of misalignment estimated to cause an error in measurement of at least 5% of the temporal horn volume, were excluded from the temporal horn study. All measures were performed by the same researcher (SAC) who was blind to the diagnosis and gender of the cases. All segmentation was carried out using a Silicon Graphics Indy workstation running a Unix operating system. Statistical analyses were carried out using the software package ‘‘SPSS’’. Total brain size was controlled for by including it as a covariate rather than by calculating ventricular-brain ratio (VBR), a procedure that has been criticised (Harvey et al., 1990; Mathalon et al., 1993).
3. Results The main result is given for each variable below (Table 2), with mention of the covariates included. The selection of these covariates for inclusion, and further testing, is described below under Artefacts and covariates. 3.1. Hemispheric volume A repeated measures ANOVA revealed an effect of sex ( F=22.2, df 1,38, p<0.01)—males having larger hemispheres than females. There was no significant effect of diagnosis, and no interaction between diagnosis and sex. No differences involving side were found within subjects. ANCOVA indicated that age at death was a significant covariate of hemispheric volume ( F=10.46, df 1,38, p<0.01) with the brains of older individuals found to be smaller.
2.3. Reliability 3.2. Ventricular volume Evidence of intra-rater reliability was obtained by repeating segmentations of four hemispheres and five lateral ventricles. Comparison of hemisphere volumes gave an intraclass correlation of >0.99. Comparison of lateral ventricle measures and temporal horn measures also gave intraclass correlations of 0.99.
The measures of ventricle volume failed the Box’s M-test for homogeneity of variance. The natural logarithms of these measures were used instead, which gave a satisfactory Box’s M-test result. A repeated measures ANOVA found lateral ventricular
Table 2 Table of mean data values also showing standard deviations and sample sizes Variable Hemisphere volume (cm3) Lateral ventricle volume (cm3) Temporal horn volume (cm3) Temporal horn as a percentage of lateral ventricle
Comparison males (n=10)a
Schizophrenic males (n=14)b
Comparison females (n=10)
Schizophrenic females (n=9)c
Left
576.9F45.5
578.7F70.1
489.5F68.7
448.3F75.3
Right Left
574.3F44.5 11.9F3.3
580.6F66.4 13.0*F3.0
487.0F68.2 9.6F3.4
447.2F73.9 20.1**F7.7
Right Left
10.6F2.2 0.69F0.49
12.1*F3.7 0.82*F0.28
8.5F3.5 0.64F0.27
18.9**F7.7 1.06*F0.56
Right Left
0.85F0.46 5.9F3.2
1.13*F0.33 6.7F2.9
0.54F0.38 7.3F3.8
1.24*F0.59 5.2F2.4
6.5F3.8
6.6F2.1
Right
8.1**F4.5
10.3**F5.0
Values are actual measured values uncorrected for tissue shrinkage. a n=9 in measures dependent on the trigone. b n=13 in measures dependent on the trigone. c n=8 in measures dependent on the trigone. * p<0.01 effect of diagnosis. ** Statistically significant interaction; sex side or sex diagnosis (see Results for details).
S.A. Chance et al. / Schizophrenia Research 62 (2003) 123–131
enlargement in the cases with schizophrenia ( F=34.9, df 1,37, p<0.01). No sex difference was found, but there was an interaction between diagnosis and sex ( F=6.8, df 1,37, p=0.01), indicating that the ventricular enlargement was markedly greater in female patients (see Fig. 3). Age at death and total brain volume were included as covariates in these tests. ANCOVA of log ventricular volume showed that total brain volume was a significant covariate ( F=6.1, df 1,37, p<0.05) due to a positive correlation between brain size and ventricular volume in controls (r=0.55, p=0.01) and a negative correlation in cases with schizophrenia (r= 0.46, p=0.03). Older age at death was significantly associated with larger ventricles ( F=21.1, df 1,37, p<0.01). 3.3. Temporal horn volumes Temporal horn enlargement was present in cases with schizophrenia ( F=8.4, df 1,34, p<0.01) as demonstrated by repeated measures ANOVA (Fig. 4). No sex differences were revealed, and no interaction between diagnosis and sex was found. Both age at death and total brain volume were controlled for, although neither were found to be significant covariates by ANCOVA. In view of the expected selectivity of the enlargement to the temporal horns, it was anticipated that the temporal horn would make up different percentages of the lateral ventricle total in each hemisphere. A repeated measures ANOVA of percentage volume (temporal horn/lateral ventricle) on the 40 cases that
Fig. 3. Graph illustrating that female schizophrenics show a marked increase in total lateral ventricular volume compared to other groups.
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Fig. 4. The temporal horn enlargement was not significantly greater on the left side.
had temporal horn measures found an asymmetry effect. The right temporal horn contributes a greater part of the lateral ventricle, and an interaction between sex and side revealed this was more apparent in males ( F=6.1, df 1,36, p<0.05). Age at death was controlled for although it was not a significant covariate of relative temporal horn volume. To investigate differences between temporal horn enlargement and total lateral ventricular enlargement in schizophrenia, volumes in the cases were compared by correlation analysis. The correlation of temporal horn volume with lateral ventricular volume did not reach significance (r=0.41, p=0.07). 3.4. Temporal gyri volume correlates Previous studies of brains from this series found loss of gyral volume in the temporal lobe in schizophrenia—in the superior temporal (Highley et al., 1999), fusiform and parahippocampal gyri (McDonald et al., 2000). For the subgroups that had both measures (12 controls and 18 patients), a relationship between these measures and ventricle volumes was tested by correlation analysis. Total lateral ventricle and temporal horn volumes were compared with the average measures of each gyrus. For lateral ventricle volume, there were nonsignificant but mainly positive correlations in comparison subjects and strongly negative correlations in patients (STG r= 0.51, p<0.05; PHG r= 0.45, p=0.06; Fusiform r= 0.6, p<0.01). There were no correlations with temporal horn volume. Analysis of each hemisphere
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separately showed the reversed correlation to be strongest for the superior temporal gyrus and lateral ventricle on the left (r=0.57, p=0.06 in comparison subjects and r= 0.46, p=0.06 in patients). 3.5. Age of onset Since previous studies on these brains revealed neuroanatomical abnormalities related to age of onset (Highley et al., 1998b), a correlation analysis was performed for each of the volume variables (Fig. 5). A positive correlation was found between age of onset and total ventricular volume (r=0.58, p<0.01) but not between age of onset and temporal horn volume (r=0.33, p=0.16). A further test of this variable as a partial correlation, controlling for age at death, also found a significant relationship with total ventricular volume (r=0.6, p<0.01) but not with hemisphere or temporal horn volumes. Age of onset did not differ between the sexes (t=1.1, p=0.29). 3.6. Artefacts and covariates The influence of potentially confounding variables; age at death, postmortem interval and fixation time for all cases, lifetime medication for cases with schizophrenia, and brain alignment for measures of temporal horn volume, was examined in separate ANOVAs of groups selected by sex and/or diagnosis. As already noted, females, and female patients in particular, were older at death than males. Conse-
quently, age at death was included as a covariate in all tests. Postmortem interval did not differ between groups. Fixation time was similarly examined, although the absence of accurate information led to the exclusion of four cases if this variable was included. Diagnostic groups differed significantly in fixation time ( F=9.6, df 1,35, p<0.01); however, tests of those variables that showed an effect of diagnosis (lateral ventricular volume and temporal horn volume) revealed that fixation time was not a significant covariate, and since the distortion due to fixation stabilises after approximately 3 weeks (Quester and Schroder, 1997), all of the brains studied would have reached a stable state prior to scanning. Consequently, fixation time was not treated as a covariate in the ANOVAs reported. Within the group of patients with schizophrenia, neuroleptic medication was found to have no influence on hemisphere or temporal horn volumes as a factor in repeated measures ANOVAs, but a higher lifetime neuroleptic medication rating (covarying for age) was associated with reduced lateral ventricle volume ( F=4.6, df 2,18, p<0.05). However, further analysis of lateral ventricle volume revealed that this was the result of a single female case classified as having received little lifetime medication—exclusion of this case, or inclusion of sex in the analysis, resulted in the loss of the effect. Brain alignment was assessed as an influence on temporal horn volumes in all cases, and found to have no effect between subjects ( F=0.6, df 1,38, p=0.45) or as an interaction with side ( F=0.2, df 1,38, p=0.65).
4. Discussion
Fig. 5. Graph illustrates the correlation between age of illness onset and total ventricular volume.
Lateral ventricular enlargement, as expected, was present in patients with schizophrenia. This was unaccompanied by a change in hemisphere volume, although a reduction of about 3% as reported in the meta-analysis of MRI studies of Lawrie and Abukmeil (1998) might not be detected in the sample size of the present study. Enlarged ventricles were correlated with previously reported volume reductions of temporal lobe gyri. Lateral ventricular change was significantly greater in females than in males. While there have been suggestions that neuroanatomical abnormalities, par-
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ticularly of the ventricles, are greater in males (e.g. Nopoulos et al., 1997), some studies (Andreasen et al., 1982; Gur et al., 1994; Nasrallah et al., 1990) have found greater differences of ventricular volume in females than in males. While age-related brain atrophy may contribute to the effect in females in the present study, this was controlled for in the statistical analysis. Nasrallah et al. (1990) suggested that the unusually early age of onset in their group of females, probably concomitant with greater severity of illness, might explain their finding of greater enlargement in females. The ventricles normally enlarge more in males than in females between the ages of 4 and 18 years (Giedd et al., 1996). It may be that the normal sex difference in age of onset preserves the usual sex difference in the effect of schizophrenia; however, an early female onset, as in the case of the Nasrallah study, or a relatively late male onset, as in the present study, may constitute exceptions to this rule. Although enlargement (approximately 50%) was also present in the temporal horns, this differed from the lateral ventricular change. For example: (i) It was present to an equal extent in both males and females. The lack of a sex difference is in agreement with previous postmortem studies of the temporal horn (Brown et al., 1986) and with the reduction in temporal lobe length found previously (Crow and Crow, 1996), including in these brains (Highley et al., 1998a). (ii) No relationship with age of onset was detected. In both the temporal horns and the whole ventricles, the change in schizophrenia was bilateral, i.e. the asymmetry present in the comparison group was preserved in the patient group. Although enlargement of the ventricles in schizophrenia has sometimes been found to be greater on the left (e.g. Hunter et al., 1968; Haug, 1962 in AEG studies; Buchsbaum et al., 1997; James et al., 1999 in MRI), it is generally reported as present on both sides (Suddath et al., 1989; Lawrie and Abukmeil, 1998; Wright et al., 2000). Of postmortem reports on the temporal horns, the present findings are in agreement with Brown et al. (1986) (who assessed temporal horn size on a coronal photograph) but in disagreement with Crow et al. (1989) (who assessed the area of the temporal horn
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on a radiograph from the lateral aspect and found the change to be selective to the left side). Changes in asymmetry have been associated with schizophrenia with some methods of assessment but not with others. It may be relevant that in the Crow et al. (1989) study, the ventricles had been filled (with radio-opaque medium) and this may have emphasized a change in the schizophrenic cases related to some aspect of the surrounding tissue. For example, loss of substance of the fusiform and parahippocampal gyri of the left temporal lobe (McDonald et al., 2000) may have been preferentially detected by the technique adopted by Crow et al. (1989). The enlargements found in the present study, having the appearance of greater consistency in the temporal lobes, bear comparison to the MRI analysis of ventricular enlargement by Degreef et al. (1992) who found that the changes in the temporal region had the strongest relationship to the symptoms of illness. Temporal horn enlargement, particularly on the left side, was associated with the presence of negative and, to a lesser extent, positive symptoms. Such relationships were not observed with other components of ventricular enlargement. The suggestion was made that diffuse enlargement in other areas might be related to less specific cognitive deficits. In the same series of brains of which ventricular and hemispheric volumes are reported here, change was present in both sexes within the temporal lobes—loss of gyral volume selective to the left side in the superior temporal (Highley et al., 1999), fusiform and parahippocampal gyri (McDonald et al., 2000). The present report of negative correlations between STG and lateral ventricles, and PHG and lateral ventricles in schizophrenia supports the notion that key changes in the temporal lobe are linked to diffuse enlargement of the lateral ventricles. This may also reflect the inverse relationship between total brain size and ventricle volume in schizophrenia. We postulate an effect of schizophrenia on cortical development, which depends on an interaction with sex, but is most consistently seen in the temporal lobe. For example: (i) The degree of change in the temporal horn is greater or more consistent than elsewhere in the
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ventricular system (in the present study, and see McCarley et al., 1999). (ii) The changes in size and length of the temporal lobe have been found to be greater than in the rest of the brain (Highley et al., 1998a; Bartzokis et al., 1996). (iii) Abnormalities of gyral volume and asymmetry in schizophrenia are present in the temporal lobe (McDonald et al., 2000; Highley et al., 1999) and are correlated with lateral ventricle enlargement, but are less prominent in the frontal lobes (Highley et al., 2001). Ventricular volume may be a complex derivative of the process of brain development and ageing, and this may be the reason ventricular enlargement appears to be generalised (Sanfilipo et al., 2000) and not clearly linked to volume reduction in surrounding structures (Bogerts et al., 1990, Kawasaki et al., 1993). We envisage that lateral ventricular enlargement, observed in this brain series mainly in females and related to age of onset, is linked to developmental processes that cause volume reductions of temporal lobe structures, but is also influenced by a variety of factors including sex. The change we see more consistently in both sexes in the temporal horn may reflect a core abnormality of the temporal lobe. Thus, ventricular enlargement in schizophrenia reflects abnormality of the cerebrum in general, with limited sensitivity to cortical change in specific regions influenced by sex and lateralisation.
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Ventricular enlargement in schizophrenia: a primary change in the temporal lobe? Steven A. Chance *, Margaret M. Esiri, Timothy J. Crow University of Oxford, Oxford, UK Received 15 November 2001; accepted 21 June 2002
Abstract Background: The anatomical origin of the enlargement of the cerebral ventricles in schizophrenia is obscure. Methods: In this study, the volumes of the hemispheres and lateral ventricles were assessed in MRI scans of 43 formalin-fixed brains (23 from patients and 19 comparison subjects) using a spline ‘snake’ segmentation method. Results: A bilateral ventricular volume increase was found in schizophrenia. Whereas enlargement of the lateral ventricle (mean: 54%) as a whole was related to age of onset and was greater in females than in males, enlargement of the temporal horn (mean: 54%) was not strongly related to age of onset or sex. Lateral ventricle volume was negatively correlated with STG, fusiform and parahippocampal volume in schizophrenia. Hemispheric volumes were unchanged. Conclusions: The differing correlates of the components of ventricular enlargement suggest a degree of selectivity of the disease process with a focus in the temporal lobe. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Ventricles; Parahippocampal; Sex; Gyrus; Temporal
1. Introduction Of 43 MRI studies in which lateral ventricle size was measured in schizophrenia, 77% found enlargement as did 75% of the earlier CT studies (McCarley et al., 1999). A mean increase of 26% has been estimated in MRI studies (Wright et al., 2000). Yet, the meaning for the disease process remains obscure. Lack of bimodality in the distribution of ventricular size within the patient group (Vita et al., 2000) suggests a single disease entity. Absent periventricular
* Corresponding author. Schizophrenia Research Group, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK. Tel.: +44-1865-228424; fax: +44-1865-228496. E-mail address: [email protected] (S.A. Chance).
gliosis (Roberts et al., 1987; Bruton et al., 1990) and the presence of ventricular enlargement at the time of the first episode (DeLisi et al., 1991) are consistent with a neurodevelopmental (Weinberger, 1987; Crow et al., 1989) rather than a degenerative origin. Ventricular enlargement presumably reflects a change in brain structure. There are indications that brain structural change is localised—temporal lobe volume (Dauphinais et al., 1990) and length (Crow and Crow, 1996; Highley et al., 1998a) have been found reduced relative to the brain as a whole. It has been suggested that temporal horn enlargement in schizophrenia is due to a volume reduction of adjacent limbic structures (Brown et al., 1986), and several MRI studies have found enlarged temporal horns and smaller temporal limbic structures (Bogerts et al., 1990; Kawasaki et al., 1993; Shenton et al., 1992).
0920-9964/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0920-9964(02)00344-4
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However, only Shenton et al. found a negative correlation between left temporal horn and left parahippocampal gyrus volumes, whereas the other two studies found no correlation and interpreted this as evidence against a simple interaction between limbic tissue loss and temporal horn enlargement. No correlation was also found between amygdala volume and temporal horn volume in brains from the series reported in the present study (Chance et al., 2002). This stands in contrast to the negative correlations between amygdala volume and temporal horn volume reported for epilepsy (a neurodegenerative rather than neurodevelopmental process). There is a tendency for enlargement of the ventricle to be greater on the left side (e.g. Bruton et al., 1990, DeLisi et al., 1991; Narr et al., 2001) in addition to the tendency for more marked enlargement of the temporal horns. These trends converge in studies that have found the temporal horn in the left hemisphere to be particularly enlarged (Bogerts et al., 1985; Crow et al., 1989). That the brain changes in schizophrenia have a genetic component is suggested by similar findings, e.g. a reduction in cortical grey matter (Cannon et al., 1998) and enlarged ventricles (Lawrie et al., 1999) in the siblings of patients. However, the ventricles are also found to be larger in the ill members of pairs of twins discordant for suffering from schizophrenia (Reveley et al., 1982; Suddath et al., 1990). Ventricular enlargement, therefore, and the expression of illness are dependent on both genetic and nongenetic factors (Silverman et al., 1998; Cannon et al., 1989)— perhaps better interpreted as epigenetic factors. Gender is one modulator of phenotype. Sex differences are present in both the expression of illness (i.e. in age of onset of psychosis) and the extent of abnormality of brain structure (Nopoulos et al., 1997) as well as in cerebral asymmetry (Bear et al., 1986). In this study, MRI scans from a series of postmortem brains were used to assess gross volume of the cerebral hemispheres, lateral ventricles and temporal horns to examine the selectivity of the change in ventricular structure to the temporal horns. An MRI method was chosen because this noninvasive technique allows ventricle volume to be assessed without compromising the structural integrity of the walls of the ventricles that may be distorted by dissection or the introduction of a radio-opaque medium for visualisation.
2. Methods and materials 2.1. Tissue Postmortem brains were suspended by the basilar artery for fixation in 10% formalin. Subsequent to diagnostic and pathological assessment and selection for absence of morphological distortion, the series consisted of 43 brains (from 14 male and 9 female patients with schizophrenia, and a comparison group of 10 males and 10 females). Age at death (mean in females: 73.3 years, males: 63.8 years) was treated as a covariate in later statistical analyses. Subjects were selected after assessment of clinical notes by a psychiatrist (TJC or SJ Cooper). DSM IV criteria for schizophrenia and schizoaffective disorder (one patient) were used for the selection of cases of schizophrenia. Cases were collected with the cooperation of the coroner (medical examiner) or from hospital postmortem examinations. Consent was obtained according to prevailing procedures with consent from the next-of-kin where appropriate. Pathological assessment of tissue samples was carried out by a neuropathologist (MME or B McDonald) using the CERAD criteria. All brains were confirmed to be free from major neuropathology (including Alzheimer’s disease, Parkinson’s disease and cerebrovascular disease) and free from gross morphological distortion. The degree of neuroleptic medication received during life was assessed from case notes, and categorised as little, average or much, based on a clinician’s judgement of the available clinical records (Table 1). The variability of the information available precluded a more quantitative estimation. Other potentially confounding variables, including age of symptom onset, postmortem interval and fixation time, were noted for statistical analysis. 2.2. Method Each formalin-fixed brain was scanned in a container of 10% neutral buffered formalin in a 1.5 Tesla GE Signa Advantage scanner, yielding 1.5 mm contiguous, coronal slices. The proton density weighted scanning protocol was optimised for grey-white matter contrast in formalin fixed tissue (Blamire et al., 1996). The plane of scan acquisition was approxi-
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Table 1 Demographic variables and details of the brain collection (mean and S.D.) Variable
Comparison males (n=10)
Schizophrenic males (n=14)
Comparison females (n=10)
Schizophrenic females (n=9)
Age at onset in yearsa Duration of illness in yearsa Age at death in years Postmortem interval in hours Fixation period in monthsb
NA NA 69.4F7.2 48.5F32.1 34.4F15.0
28.7F7.8 30.8F15.5 59.7F13.9 42.8F32.1 47.0F22.9
NA NA 69.9F13.8 45F25.5 27.7F16.1
32.9F10.3 44.2F13.8 77.1F13.6 40.1F36.1 55.2F23.2
a b
Inaccurate information for one case. Inaccurate information for four cases.
mated as orthogonal to the mid-sagittal plane and fronto-occipital axis as determined on a sagittal scout scan. This allowed the free-floating brain to be aligned for volume measurements of structures such as brain hemispheres and ventricles. The segmentation program was developed in Oxford University based on a so-called snake contour model. This is a semiautomated outlining method that utilises modified B-spline curves that fit to edges detected in their vicinity (i.e. the cortical surface), guided by the user (Marais, 1998). The snake outline possesses intrinsic regularising properties, which enable it to provide a smooth approximation to a boundary in the presence of image noise with subvoxel accuracy. Because the method has a limited capacity to match high velocity curves, it does not follow the
Fig. 1. A single coronal MR image of a postmortem brain, showing the spline snake program in use. The dashed line represents the spline outline; square dots on the line are the user interface for snake manipulation.
cortical surface into narrow sulci. Volume estimates were obtained as the product of multiplying snake area by slice thickness (Fig. 1). For validation, 26 brains, randomly selected from this cohort, were segmented for hemisphere volume. Total volumes of the 52 segmented hemispheres (with ventricles subtracted) were compared with estimates derived by the Archimedes principle of water displacement. Brains were dissected after scanning, the hemispheres submerged (allowing air to escape from the ventricular system), and displaced water escaped into a measuring cylinder. Statistical comparison of the two methods gave an intraclass correlation of 0.98. To define the lateral ventricles, the neck of the interventricular foramina of Monroe was used as the cut off point between lateral and third ventricles. To define the temporal horn, the first slice anterior to the trigone was used, at which point the temporal horn is distinct from the body of the lateral ventricle (Fig. 2).
Fig. 2. The position of the ventricular trigone delineated the posterior boundary of the temporal horn.
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Due to the small size of the temporal horn and its arbitrary posterior boundary, an attempt was made to limit the error due to anomalous scan alignment of the free-floating brains. Three scans, which had an angle of misalignment estimated to cause an error in measurement of at least 5% of the temporal horn volume, were excluded from the temporal horn study. All measures were performed by the same researcher (SAC) who was blind to the diagnosis and gender of the cases. All segmentation was carried out using a Silicon Graphics Indy workstation running a Unix operating system. Statistical analyses were carried out using the software package ‘‘SPSS’’. Total brain size was controlled for by including it as a covariate rather than by calculating ventricular-brain ratio (VBR), a procedure that has been criticised (Harvey et al., 1990; Mathalon et al., 1993).
3. Results The main result is given for each variable below (Table 2), with mention of the covariates included. The selection of these covariates for inclusion, and further testing, is described below under Artefacts and covariates. 3.1. Hemispheric volume A repeated measures ANOVA revealed an effect of sex ( F=22.2, df 1,38, p<0.01)—males having larger hemispheres than females. There was no significant effect of diagnosis, and no interaction between diagnosis and sex. No differences involving side were found within subjects. ANCOVA indicated that age at death was a significant covariate of hemispheric volume ( F=10.46, df 1,38, p<0.01) with the brains of older individuals found to be smaller.
2.3. Reliability 3.2. Ventricular volume Evidence of intra-rater reliability was obtained by repeating segmentations of four hemispheres and five lateral ventricles. Comparison of hemisphere volumes gave an intraclass correlation of >0.99. Comparison of lateral ventricle measures and temporal horn measures also gave intraclass correlations of 0.99.
The measures of ventricle volume failed the Box’s M-test for homogeneity of variance. The natural logarithms of these measures were used instead, which gave a satisfactory Box’s M-test result. A repeated measures ANOVA found lateral ventricular
Table 2 Table of mean data values also showing standard deviations and sample sizes Variable Hemisphere volume (cm3) Lateral ventricle volume (cm3) Temporal horn volume (cm3) Temporal horn as a percentage of lateral ventricle
Comparison males (n=10)a
Schizophrenic males (n=14)b
Comparison females (n=10)
Schizophrenic females (n=9)c
Left
576.9F45.5
578.7F70.1
489.5F68.7
448.3F75.3
Right Left
574.3F44.5 11.9F3.3
580.6F66.4 13.0*F3.0
487.0F68.2 9.6F3.4
447.2F73.9 20.1**F7.7
Right Left
10.6F2.2 0.69F0.49
12.1*F3.7 0.82*F0.28
8.5F3.5 0.64F0.27
18.9**F7.7 1.06*F0.56
Right Left
0.85F0.46 5.9F3.2
1.13*F0.33 6.7F2.9
0.54F0.38 7.3F3.8
1.24*F0.59 5.2F2.4
6.5F3.8
6.6F2.1
Right
8.1**F4.5
10.3**F5.0
Values are actual measured values uncorrected for tissue shrinkage. a n=9 in measures dependent on the trigone. b n=13 in measures dependent on the trigone. c n=8 in measures dependent on the trigone. * p<0.01 effect of diagnosis. ** Statistically significant interaction; sex side or sex diagnosis (see Results for details).
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enlargement in the cases with schizophrenia ( F=34.9, df 1,37, p<0.01). No sex difference was found, but there was an interaction between diagnosis and sex ( F=6.8, df 1,37, p=0.01), indicating that the ventricular enlargement was markedly greater in female patients (see Fig. 3). Age at death and total brain volume were included as covariates in these tests. ANCOVA of log ventricular volume showed that total brain volume was a significant covariate ( F=6.1, df 1,37, p<0.05) due to a positive correlation between brain size and ventricular volume in controls (r=0.55, p=0.01) and a negative correlation in cases with schizophrenia (r= 0.46, p=0.03). Older age at death was significantly associated with larger ventricles ( F=21.1, df 1,37, p<0.01). 3.3. Temporal horn volumes Temporal horn enlargement was present in cases with schizophrenia ( F=8.4, df 1,34, p<0.01) as demonstrated by repeated measures ANOVA (Fig. 4). No sex differences were revealed, and no interaction between diagnosis and sex was found. Both age at death and total brain volume were controlled for, although neither were found to be significant covariates by ANCOVA. In view of the expected selectivity of the enlargement to the temporal horns, it was anticipated that the temporal horn would make up different percentages of the lateral ventricle total in each hemisphere. A repeated measures ANOVA of percentage volume (temporal horn/lateral ventricle) on the 40 cases that
Fig. 3. Graph illustrating that female schizophrenics show a marked increase in total lateral ventricular volume compared to other groups.
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Fig. 4. The temporal horn enlargement was not significantly greater on the left side.
had temporal horn measures found an asymmetry effect. The right temporal horn contributes a greater part of the lateral ventricle, and an interaction between sex and side revealed this was more apparent in males ( F=6.1, df 1,36, p<0.05). Age at death was controlled for although it was not a significant covariate of relative temporal horn volume. To investigate differences between temporal horn enlargement and total lateral ventricular enlargement in schizophrenia, volumes in the cases were compared by correlation analysis. The correlation of temporal horn volume with lateral ventricular volume did not reach significance (r=0.41, p=0.07). 3.4. Temporal gyri volume correlates Previous studies of brains from this series found loss of gyral volume in the temporal lobe in schizophrenia—in the superior temporal (Highley et al., 1999), fusiform and parahippocampal gyri (McDonald et al., 2000). For the subgroups that had both measures (12 controls and 18 patients), a relationship between these measures and ventricle volumes was tested by correlation analysis. Total lateral ventricle and temporal horn volumes were compared with the average measures of each gyrus. For lateral ventricle volume, there were nonsignificant but mainly positive correlations in comparison subjects and strongly negative correlations in patients (STG r= 0.51, p<0.05; PHG r= 0.45, p=0.06; Fusiform r= 0.6, p<0.01). There were no correlations with temporal horn volume. Analysis of each hemisphere
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separately showed the reversed correlation to be strongest for the superior temporal gyrus and lateral ventricle on the left (r=0.57, p=0.06 in comparison subjects and r= 0.46, p=0.06 in patients). 3.5. Age of onset Since previous studies on these brains revealed neuroanatomical abnormalities related to age of onset (Highley et al., 1998b), a correlation analysis was performed for each of the volume variables (Fig. 5). A positive correlation was found between age of onset and total ventricular volume (r=0.58, p<0.01) but not between age of onset and temporal horn volume (r=0.33, p=0.16). A further test of this variable as a partial correlation, controlling for age at death, also found a significant relationship with total ventricular volume (r=0.6, p<0.01) but not with hemisphere or temporal horn volumes. Age of onset did not differ between the sexes (t=1.1, p=0.29). 3.6. Artefacts and covariates The influence of potentially confounding variables; age at death, postmortem interval and fixation time for all cases, lifetime medication for cases with schizophrenia, and brain alignment for measures of temporal horn volume, was examined in separate ANOVAs of groups selected by sex and/or diagnosis. As already noted, females, and female patients in particular, were older at death than males. Conse-
quently, age at death was included as a covariate in all tests. Postmortem interval did not differ between groups. Fixation time was similarly examined, although the absence of accurate information led to the exclusion of four cases if this variable was included. Diagnostic groups differed significantly in fixation time ( F=9.6, df 1,35, p<0.01); however, tests of those variables that showed an effect of diagnosis (lateral ventricular volume and temporal horn volume) revealed that fixation time was not a significant covariate, and since the distortion due to fixation stabilises after approximately 3 weeks (Quester and Schroder, 1997), all of the brains studied would have reached a stable state prior to scanning. Consequently, fixation time was not treated as a covariate in the ANOVAs reported. Within the group of patients with schizophrenia, neuroleptic medication was found to have no influence on hemisphere or temporal horn volumes as a factor in repeated measures ANOVAs, but a higher lifetime neuroleptic medication rating (covarying for age) was associated with reduced lateral ventricle volume ( F=4.6, df 2,18, p<0.05). However, further analysis of lateral ventricle volume revealed that this was the result of a single female case classified as having received little lifetime medication—exclusion of this case, or inclusion of sex in the analysis, resulted in the loss of the effect. Brain alignment was assessed as an influence on temporal horn volumes in all cases, and found to have no effect between subjects ( F=0.6, df 1,38, p=0.45) or as an interaction with side ( F=0.2, df 1,38, p=0.65).
4. Discussion
Fig. 5. Graph illustrates the correlation between age of illness onset and total ventricular volume.
Lateral ventricular enlargement, as expected, was present in patients with schizophrenia. This was unaccompanied by a change in hemisphere volume, although a reduction of about 3% as reported in the meta-analysis of MRI studies of Lawrie and Abukmeil (1998) might not be detected in the sample size of the present study. Enlarged ventricles were correlated with previously reported volume reductions of temporal lobe gyri. Lateral ventricular change was significantly greater in females than in males. While there have been suggestions that neuroanatomical abnormalities, par-
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ticularly of the ventricles, are greater in males (e.g. Nopoulos et al., 1997), some studies (Andreasen et al., 1982; Gur et al., 1994; Nasrallah et al., 1990) have found greater differences of ventricular volume in females than in males. While age-related brain atrophy may contribute to the effect in females in the present study, this was controlled for in the statistical analysis. Nasrallah et al. (1990) suggested that the unusually early age of onset in their group of females, probably concomitant with greater severity of illness, might explain their finding of greater enlargement in females. The ventricles normally enlarge more in males than in females between the ages of 4 and 18 years (Giedd et al., 1996). It may be that the normal sex difference in age of onset preserves the usual sex difference in the effect of schizophrenia; however, an early female onset, as in the case of the Nasrallah study, or a relatively late male onset, as in the present study, may constitute exceptions to this rule. Although enlargement (approximately 50%) was also present in the temporal horns, this differed from the lateral ventricular change. For example: (i) It was present to an equal extent in both males and females. The lack of a sex difference is in agreement with previous postmortem studies of the temporal horn (Brown et al., 1986) and with the reduction in temporal lobe length found previously (Crow and Crow, 1996), including in these brains (Highley et al., 1998a). (ii) No relationship with age of onset was detected. In both the temporal horns and the whole ventricles, the change in schizophrenia was bilateral, i.e. the asymmetry present in the comparison group was preserved in the patient group. Although enlargement of the ventricles in schizophrenia has sometimes been found to be greater on the left (e.g. Hunter et al., 1968; Haug, 1962 in AEG studies; Buchsbaum et al., 1997; James et al., 1999 in MRI), it is generally reported as present on both sides (Suddath et al., 1989; Lawrie and Abukmeil, 1998; Wright et al., 2000). Of postmortem reports on the temporal horns, the present findings are in agreement with Brown et al. (1986) (who assessed temporal horn size on a coronal photograph) but in disagreement with Crow et al. (1989) (who assessed the area of the temporal horn
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on a radiograph from the lateral aspect and found the change to be selective to the left side). Changes in asymmetry have been associated with schizophrenia with some methods of assessment but not with others. It may be relevant that in the Crow et al. (1989) study, the ventricles had been filled (with radio-opaque medium) and this may have emphasized a change in the schizophrenic cases related to some aspect of the surrounding tissue. For example, loss of substance of the fusiform and parahippocampal gyri of the left temporal lobe (McDonald et al., 2000) may have been preferentially detected by the technique adopted by Crow et al. (1989). The enlargements found in the present study, having the appearance of greater consistency in the temporal lobes, bear comparison to the MRI analysis of ventricular enlargement by Degreef et al. (1992) who found that the changes in the temporal region had the strongest relationship to the symptoms of illness. Temporal horn enlargement, particularly on the left side, was associated with the presence of negative and, to a lesser extent, positive symptoms. Such relationships were not observed with other components of ventricular enlargement. The suggestion was made that diffuse enlargement in other areas might be related to less specific cognitive deficits. In the same series of brains of which ventricular and hemispheric volumes are reported here, change was present in both sexes within the temporal lobes—loss of gyral volume selective to the left side in the superior temporal (Highley et al., 1999), fusiform and parahippocampal gyri (McDonald et al., 2000). The present report of negative correlations between STG and lateral ventricles, and PHG and lateral ventricles in schizophrenia supports the notion that key changes in the temporal lobe are linked to diffuse enlargement of the lateral ventricles. This may also reflect the inverse relationship between total brain size and ventricle volume in schizophrenia. We postulate an effect of schizophrenia on cortical development, which depends on an interaction with sex, but is most consistently seen in the temporal lobe. For example: (i) The degree of change in the temporal horn is greater or more consistent than elsewhere in the
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ventricular system (in the present study, and see McCarley et al., 1999). (ii) The changes in size and length of the temporal lobe have been found to be greater than in the rest of the brain (Highley et al., 1998a; Bartzokis et al., 1996). (iii) Abnormalities of gyral volume and asymmetry in schizophrenia are present in the temporal lobe (McDonald et al., 2000; Highley et al., 1999) and are correlated with lateral ventricle enlargement, but are less prominent in the frontal lobes (Highley et al., 2001). Ventricular volume may be a complex derivative of the process of brain development and ageing, and this may be the reason ventricular enlargement appears to be generalised (Sanfilipo et al., 2000) and not clearly linked to volume reduction in surrounding structures (Bogerts et al., 1990, Kawasaki et al., 1993). We envisage that lateral ventricular enlargement, observed in this brain series mainly in females and related to age of onset, is linked to developmental processes that cause volume reductions of temporal lobe structures, but is also influenced by a variety of factors including sex. The change we see more consistently in both sexes in the temporal horn may reflect a core abnormality of the temporal lobe. Thus, ventricular enlargement in schizophrenia reflects abnormality of the cerebrum in general, with limited sensitivity to cortical change in specific regions influenced by sex and lateralisation.
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