University of Oxford, UK
Correspondence: Steven A. Chance, Schizophrenia Research Group, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK. Tel: 01865228424; fax: 01865 228496; e-mail: steven.chance{at}clneuro.ox.ac.uk
Declaration of interest This work was supported by the Medical Research Council and the SANE Trust.
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ABSTRACT |
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Aims To assess the volume of the amygdala in a series of brains post-mortem.
Method Amygdala volume was estimated using point-counting in both hemispheres of the brains of 10 male and 8 female patients with schizophrenia, and a comparison group of 9 males and 9 females.
Results No significant reduction of amygdala volume was found.
Conclusions Significant volume reduction of the amygdala is not a consistent feature of schizophrenia; findings from early MRI studies using coarse delineation methods may introduce bias to subsequent meta-analyses.
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INTRODUCTION |
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METHOD |
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Subsequent to sectioning and staining, the series consisted of 36 cases, comprising 10 men and 8 women with schizophrenia, and a comparison group of 9 men and 9 women.
The degree of neuroleptic medication received during life was assessed from case notes, and categorised as little, average or much. This was based on a clinician's (T.J.C. or S.A.C.) judgement on the basis of the available clinical records, the variability of information available precluding a more quantitative estimation. A three-section categorisation of causes of death indicates that 14 subjects died of cardiac causes, 9 of respiratory causes and 12 of other causes. Of these, 22 deaths were prolonged and 13 were sudden. One subject died of uncertain causes. Other demographic details and potentially confounding variables, including age of symptom onset, duration of illness, age at death, post-mortem interval and fixation time, were noted for statistical analysis (Table 1).
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Tissue preparation
Following removal of the leptomeninges and brain-stem, and bisection of the
brain, the temporal lobes were removed from the rest of the hemispheres at the
posterior end of the sylvian fissure. The temporal lobe was cut into slices 5
mm thick along its anteroposterior axis. Embedding the slices in paraffin
resulted in blocks of tissue approximately 3 mm thick owing to shrinkage.
Blocks containing the amygdala were exhaustively sectioned from a position
posterior to, and random with respect to, the posterior border of the
amygdala. For a structure with a regular shape such as the amygdala, a sample
of approximately 10 sections should be adequate for the estimation of volume
(Gundersen & Jensen,
1987). Selecting sections 25 µm thick with an interslice
distance of 650 µm provided about 8-12 sections per amygdala. The sections
were counterstained with Luxol fast blue, a myelin stain useful for picking
out fibre tracts, and cresyl violet, which stains Nissl's substance in cell
bodies (Fig. 1) (reagents
obtained from Raymond A. Lamb Ltd, Eastbourne, UK).
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Measurement
A Cavalieri estimate of volume for each amygdala was obtained by
stereological point-counting within the bounds of the amygdala on all sections
in which it appeared. A 4-mm2 point density grid printed on acetate
was laid over each cross-section and viewed under a dissecting microscope
x7 magnification (Fig.
2). Each point represented a volume of 10.8 mm3 (4 mm
x 4 mm x 0.675 mm). Three placements of the grid, each time in a
random orientation, were used to obtain a mean count for each section. The
total count was multiplied by the volume represented by each point for an
estimate of total volume. The most anterior section containing the hippocampus
and the most anterior section containing the temporal horn were also noted.
This enabled a calculation to be made of the percentage of amygdala volume
overlapping with each of those structures along the axis of the temporal
lobe.
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All measures were performed by the same researcher (S.A.C.) who was blind to the diagnosis and gender of the cases. Left, right and mean amygdala volumes were obtained.
Pilot study
A pilot study was used to determine the grid size of points and the number
of counts per section required for a satisfactory estimate of amygdala volume.
Point counts were made for each of three different grid sizes, varying the
number of recounts. Trial grid sizes had interpoint distances of 2 mm, 3 mm
and 4 mm, respectively. The 4-mm2 grid yielded a total point count
of up to about 75 points per amygdala. Three counts of this grid gave a
coefficient of error of 0.04, which was deemed satisfactory.
Reliability
The volume was estimated twice for 10 randomly selected amygdalas to test
intrarater reliability. This provided an intraclass correlation coefficient of
0.94, suggesting that the reliability of this measure was satisfactory.
Statistics
Statistical analyses were carried out using the software Statistical
Package for the Social Sciences, version 9.0
(SPSS, 1998). Unfortunately,
for some amygdalas, insufficient tissue was available to provide a
systematically random sample of total volume. This was due to an idiosyncratic
tissue response to embedding procedures in some tissue blocks which resulted
in unsatisfactory sections in a few amygdalas and prohibited their inclusion.
Consequently, three cases provided volumetric data only for the right side and
four cases only for the left side. Since a repeated-measures analysis of
variance (ANOVA) would exclude all seven cases with one side missing, an
alternative univariate ANOVA was used to test the mean of both sides for each
case, replaced by the value for just one side in cases that did not have both.
This approach was used to test for the between-subject effects of diagnosis
and gender. A repeated-measures ANOVA was still applied to test the
within-subject effects of side using those cases that had data for both sides.
In addition, an asymmetry statistic was calculated for these cases:
(RL)/(R+L) x 100, where R and
L are the values for the right and left sides respectively.
The influence of potentially confounding variables age at death, post-mortem interval and fixation time for all cases were examined as variables in separate ANOVAs of groups selected by gender and/or diagnosis. Lifetime medication of the patients with schizophrenia was examined as a factor in ANOVA of the measured variables. Clinical information was felt to be unsatisfactory for correlating symptoms or sub-syndromes with data. All variables, including covariates, fitted with a normal distribution as tested by a KolmogorovSmirnov goodness-of-fit test (Zar, 1984) for each gender and diagnosis group. Homogeneity of variance of the measured variables between groups was accepted after testing with a Box's M test (Glantz & Slinker, 2000) before each ANOVA.
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RESULTS |
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Accuracy
The observed coefficients of error for the estimates of volume were less
than or equal to 0.1 for both left and right amygdalas in each diagnosis
x gender subgroup, indicating that their means offer a satisfactory
estimate of the true population means.
Results of analysis of variance
A univariate ANOVA of mean amygdala volume found no significant difference
between schizophrenia cases and controls (F=0.5, d.f. 1,30,
P=0.47), no difference between genders (F=0.1, d.f. 1,30,
P=0.73) and no interaction between diagnosis and gender. Analysis of
covariance (ANCOVA) included fixation time, which was not a significant
covariate, and age, which showed a significant negative relationship with
volume (F=5.4, d.f. 1,30, P=0.03). Inclusion of brain volume
in a secondary ANCOVA revealed that it was a significant covariate
(F=10.8, d.f. 1,29, P<0.01) which had a positive
relationship with amygdala volume, and resulted in a reduced P value
in the effect of age (F=0.9, d.f. 1,29, P=0.37), suggesting
a relationship with age described below. When controlling for brain volume all
other results remained, including the lack of difference between patients and
controls, and between the genders.
A repeated-measures ANOVA revealed no significant volume asymmetry of the amygdala and no difference in amygdala symmetry between groups. An ANCOVA found that age and fixation time were not significant covariates (although there was an interaction between fixation time and side: left amygdala smaller with longer fixation time, F=8.8, d.f. 1,22, P<0.01). Brain volume also had no effect on amygdala asymmetry.
The percentage of mean amygdala volume overlapping with the hippocampus, along the temporal lobe axis, was 56% (s.d. 15) in control brains and 63% (s.d. 17) in schizophrenia. The volume overlap with the temporal horn of the ventricles was 76% (s.d. 12) in controls and 84% (s.d. 12) in schizophrenia. No significant correlations were found between amygdala volumes and temporal horn volumes.
Artefacts and covariates
As shown in Table 1, the
women (F=7.0, d.f. 1,32, P=0.01), particularly those with
schizophrenia (F=3.7, d.f. 1,32, P=0.06), were older at
death than the men. Consequently, age at death was included as a covariate in
all tests of the measured variables. As expected, the total brain volumes were
larger in the men than in the women in this series. Amygdala volume was
positively correlated with brain volume, which was included as a covariate in
secondary ANOVAs of the measured variables to observe the effect of
controlling for brain size that might mask changes in the amygdala.
Post-mortem factors
Post-mortem interval did not differ between groups and therefore was not
included as a covariate. Fixation time was similarly examined and differed
between groups selected by diagnosis (F=25.4, d.f. 1,32,
P<0.01) and gender (F=4.0, d.f. 1,32, P=0.06).
Consequently, although the distortion due to fixation stabilises after
approximately 3 weeks (Quester &
Schroder, 1997) and all of the brains studied should therefore
have reached a stable state prior to examination, fixation time was included
as a covariate in the analysis of amygdala volume.
Clinical factors
Within the group of patients with schizophrenia, age of illness onset and
neuroleptic medication were found to have no influence on the mean amygdala
volume or the asymmetry of amygdala volumes. The mean level of medication
within the schizophrenia group corresponded to a rating of
average or much.
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DISCUSSION |
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In contrast, the post-mortem study by Heckers et al (1990) found no difference in the volume of the amygdala in 20 patients (see Table 4). Similarly, Pakkenberg's post-mortem planimetry study (Pakkenberg, 1990) found no difference in volume of the basolateral nucleus, which constitutes a large percentage of the amygdala (the cortico-basolateral nuclei constitute 75% according to Eccles, 1989). These differ from the original finding of reduced amygdala volume in post-mortem material (Bogerts et al, 1985).
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Contrary to what might be expected if schizophrenia is a disorder of the limbic system, no volumetric reduction in the amygdala was found in this set of brains. If sustained, this conclusion suggests that the structural changes that have been established in post-mortem studies (Brown et al, 1986; Altshuler et al, 1990), including those of the parahippocampal gyrus in brains from this collection (McDonald et al, 2000), do not extend equally to other parts of the limbic system such as the amygdala and, as previously indicated, may not substantively involve the fornix (Chance et al, 1999).
MRI limitations
Although consistent with other post-mortem findings
(Heckers et al, 1990; Pakkenberg, 1990) the absence
of a reduction of amygdala size apparently runs counter to the weight of
published neuro-imaging research. Recent MRI reviews and meta-analyses include
studies from the early 1990s, since which time imaging technology has
improved. The most obvious limitations of older studies is low scan
resolution. Several studies provide only one or two slices through the
amygdala (Table 3). Such
limited sampling exacerbates the problem of delineating the amygdala,
separating it from the hippocampus and the temporal horn of the ventricle.
Several authors concluded that the delineation of the amygdala was unreliable
and excluded it from their analysis (Flaum
et al, 1995), or excluded the region of overlap with the
hippocampus (Breier et al,
1992). Many studies (e.g.
DeLisi et al, 1991)
simply included it with the hippocampus. Some studies (e.g. Bogerts et
al, 1990,
1993;
Seidman et al, 1999)
that divided a segmentation including both amygdala and hippocampus into a
posterior portion and an anterior portion (deemed to represent the amygdala)
found a volume reduction only when the posterior portion was included.
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Table 3 surveys the MRI studies from the period 1988-2000 that have measured the volume of the amygdala in schizophrenia. Studies that provided only one or two slices through the amygdala have been noted. The outcome of the study is reported for the measurement deemed to be closest to an amygdala volume. In some cases this is the anterior part of a hippocampusamygdala complex. In studies in which the amygdala was defined as a separate entity, the landmark used for the posterior boundary is important. An interslice spacing has been reported for studies that measured more than one slice through the amygdala. The interslice spacing is composed of both slice thickness and, when present, interslice gap, and is split into categories of less than or greater than 3 mm, since a distance greater than 3 mm has been reported to reduce significantly the accuracy of MRI measurements (Luft et al, 1996).
Limitations of meta-analysis
Although apparently consistent evidence of amygdala volume reduction
emerges from compilations of studies, such meta-analyses conceal a potential
source of bias. In most studies a landmark external to the temporal lobe was
used either to mark the division into anterior and posterior portions, or to
begin segmentation of the amygdala. Few MRI studies that provide more than two
slices through the amygdala delineate it without the use of an external
landmark (Fig. 4). The
landmarks include the mamillary bodies (Bogerts et al,
1990,
1993;
Shenton et al, 1992;
Rossi et al, 1994;
Becker et al, 1996;
Hirayasu et al,
1998), the optic tract (Staal
et al, 2000), the pons
(Hoff et al, 1992),
and the anterior and posterior commissures
(Seidman et al,
1999). However, the temporal lobes have been reported to be
preferentially shortened in schizophrenia
(Bartzokis et al,
1996). For example, in the present series of brains, measurement
from the pole to the posterior sylvian fissure
(Highley et al,
1998), and to the ventricular trigone (further details available
from the author upon request), have found shorter temporal lobes despite
controlling for brain size. In this situation, landmarks that lie outside the
temporal lobe in cases of schizophrenia will be further forwards relative to
structures within the temporal lobe. Consequently, the use of external
landmarks in MRI studies could constitute one systematic source of error,
yielding smaller estimates of amygdala volume such as are identified in the
meta-analyses.
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Furthermore, this study found that at least half of the volume of the amygdala overlaps the hippocampus along the axis of the temporal lobe. This emphasises the necessity of clearly differentiating the two structures to obtain accurate volumes. Although the mean amygdala volume was not changed in this study, the percentage of its volume overlapped by the neighbouring hippocampus and temporal horn was slightly more in the brains from subjects who had schizophrenia. The greater surface of amygdala bordered by the high contrast of an enlarged temporal horn in schizophrenia could lead to a more conservative segmentation of the amygdala on MRI scans.
Hemisphere and gender
No significant asymmetry of amygdala volume was found in these brains
a finding similar to that of Heckers et al
(1990). No difference of
asymmetry was noted between patients with schizophrenia and comparison
subjects. In contrast to the finding of Fukuzako et al
(1997), who showed that a
relatively larger right hippocampus was correlated with later age of illness
onset, no correlation between amygdala asymmetry and age of onset was found.
This was accompanied by an absence of significant difference between the
genders, similar to the findings of Bryant et al
(1999), although the mean
amygdala volume in the women seemed to be a little less than that in the men
(see Table 2)
presumably associated with the normal human sexual dimorphism of total brain
size.
Interpreting normal volume
The negative findings of this study (particularly in relation to imaging
studies) raise the possibility of a type II error (i.e. a failure to identify
a difference between groups because of small sample size). A power analysis
using the Statmate program, version 1.01 (GraphPad Software, San
Diego, USA) indicates that this study had about 15% power to detect a change
of 5-7% of amygdala volume, as suggested by MRI meta-analyses. This rises to
about 30% power to detect a change of 10% volume, and 80% power to detect a
change of 20% (power=1 - p (type II error); the model was a
two-samples t-test with =0.05). The observed coefficients of
error, which take into account sample size to determine how good an estimate
of the true population mean is provided by the sample mean, were all
satisfactory, at less than or equal to 0.1.
The absence of a gross volumetric reduction in this study does not discount
a cytoarchitectural or neurochemical disturbance. Increased dopamine
innervations on the left (Reynolds,
1983) and reduced binding of -aminobutyric acid
(Simpson et al, 1989)
in the amygdala in schizophrenia, have been interpreted as a loss of
inhibition which might induce positive symptoms
(Reynolds, 1995). Such changes
may reflect a change in connectivity, for example of the dopaminergic afferent
fibres, rather than an alteration in gross volume.
The study was limited by the use of elderly, medicated subjects, and Bogerts et al (1991) have suggested that age-related brain atrophy may obscure reductions in limbic structures. In our study the negative association of age with volume could act to reduce any apparent diminution in volume in the subjects with schizophrenia, since the control subjects were on average 5 years older (means: controls 69 years, patients 64 years). However, age was controlled for as a covariate in the analyses of volume. The use of MRI can avoid these complications.
Magnetic resonance imaging is most appropriate for assessment of macroscopic measurements, while post-mortem examination is still the only option at a microscopic scale. Currently, the amygdala stands at the limit of structures that can be satisfactorily determined using MRI. Recent and improving methods of assessment, which make use of visual tracing of the amygdalahippocampus boundary, using the alveus and local anatomical features rather than other external landmarks, should provide a more reliable source of measurements (Kates et al, 1997; Niemann et al, 2000; Pruessner et al, 2000). Further studies are required to clarify which, if any, components of the limbic system are affected in schizophrenia. The current study supports the conclusion that volume reductions of the amygdala in schizophrenia are not large, and that small reductions reported in MRI may be due to coarse delineation methods that could introduce bias to subsequent meta-analyses.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication May 14, 2001. Revision received September 24, 2001. Accepted for publication September 27, 2001.
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