Research Laboratory for Stereology and Neuroscience, Bispebjerg Unversity Hospital, Copenhagen, and Stereological Research Laboratory, Aarhus University, Aarhus, Denmark
Correspondence: Birgitte Bo Andersen, Research Laboratory for Stereology and Neuroscience, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. Tel: +45 3531 6420; fax: +45 3531 6434; e-mail: forsklab{at}bbh.hosp.dk
Declaration of interest This work was supported by the Hartmann Brothers Foundation, the Stanley Foundation and the I. M. K. Almene Fund.
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ABSTRACT |
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Aims To provide stereological estimations of volumes and cell number in the cerebella of people with schizophrenia and a control group using post-mortem material.
Method Stereological methods were applied to cerebella taken from eight male patients with a DSMIII diagnosis of chronic schizophrenia with no neurological disorder (mean age 57.5 years) and ten male controls (mean age 56.2 years). The Cavalieri principle was used to provide estimates of volumes, the optical disector method to obtain estimates of the numerical density of Purkinje and granule cells, and a combination of the two to obtain estimates of total cell numbers in the cerebellum. The rotator method was applied to obtain estimates of mean Purkinje cell volume.
Results No global structural difference in major volumes, cell numbers of Purkinje cell volume was found between the groups.
Conclusions The most frequently reported pathological finding in the cerebellum in schizophrenia is vermal atrophy, which was not found in this small group of heavily affected patients.
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INTRODUCTION |
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The aim of this study was to apply recent stereological methods to cerebella from people with schizophrenia and an age- and gender-matched control group. The methods used were the Cavalieri principle (Gundersen et al, 1988b) to estimate the major volumes, the optical disector method (Gundersen, 1986) to obtain estimates of the numerical density of granular and Purkinje cells, and a combination of the two to obtain estimates of total cell numbers. The rotator method (Jensen & Gundersen, 1993) was applied to estimate mean Purkinje cell volume.
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METHOD |
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In the schizophrenia group the brain samples were taken from people with a DSMIII diagnosis of schizophrenia (American Psychiatric Association, 1980) who were in-patients at a psychiatric hospital in Denmark. All of these patients had been treated with neuroleptic drugs for a period of 3-30 years. The clinical data on both study groups are shown in Tables 1 and 2. The numbers of insulin comas and applications of electroconvulsive therapy (ECT) are given in Table 1, and post-mortem interval, fixation time and agonal state are presented in Table 2.
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Neuropathology
Tissue blocks were sampled from frontal, parietal, medial, temporal and
occipital lobes, the insula, cingulate gyrus and hippocampus, and one or two
tiers of mesencephalon. The tissue was processed routinely and embedded in
paraffin wax. Sections 4 µm thick were cut from all blocks for haematoxylin
and eosin stains, and from selected areas for immunohistochemical
investigation. Sections 8 µm thick were cut from all blocks for
KluverBarrera staining. Immunohistochemical stains were used for
beta-amyloid (DAKO M0872; 1:200), tau (DAKO A0024, 1:50 000), ubiquitin (DAKO
Z0458, 1:5000) and alphasynuclein (Zymed zs 18-0215, 1:2000) (DAKO, Glostrup,
Denmark; Zymed, San Francisco, CA, USA). The brain-stems were normal,
including the pigmentation of the substantia nigra. There were no tumour or
neuronal or glial inclusions, vasculitis or encephalitis.
Anatomy
The cerebellum consists of a median vermis and two lateral hemispheres
(Braitenberg & Atwood,
1958). Five deep fissures divide the cerebellum into lobes and
lobules: the primary fissure, the posterior superior fissure, the horizontal
fissure, the prepyramidal fissure and the posterolateral fissure. Portions of
the cerebellar hemispheres located rostrally to the primary fissure form the
anterior lobe, whereas those between the primary and the posterolateral
fissures constitute the posterior lobe. The median vermis is divided into an
anterior and a posterior part at the level of the primary fissure. The
anterior vermis is the median part of the anterior lobe, and is often
delineated by the indentation produced by the course of the medial branch of
the superior cerebellar artery. The most caudal part, the flocculonodular
lobe, is separated from the posterior lobe by the posterolateral fissure.
The motor representation in the human cerebellum is:
The cortex is made up of three layers: the outer molecular layer, the middle Purkinje single cell layer, and the inner granular layer. The Purkinje cells have a large, clear nucleus with a deeply stained nucleolus and irregular Nissl granules. The granular layer is mainly composed of closely packed granule cells, in which the nuclei form the major constituent of the cell body. The sole output cell from the cerebellar cortex is the Purkinje cell that projects to the central cerebellar nuclei, which in turn provide efferents from the cerebellum.
Experimental procedure
For all stereological estimations to be based on unbiased principles, the
procedures require isotropic, uniform random (IUR) sections, the only
exceptions being estimations of volume and total cell numbers. Most biological
structures are anisotropic, and to compensate for this the vertical section
principle was applied (Baddeley et
al, 1986). A vertical section is a plane section
perpendicular to a given horizontal plane. The horizontal plane can be defined
either by the tissue itself or generated artificially; it refers only to the
orientation of the section. All sections must be cut perpendicular to the
horizontal plane. The vertical direction must be known in all sections and the
vertical sections must have a random position and orientation in two
dimensions for the design to be unbiased. In practice, a cerebellum was
dissected from the brain-stem at the level of the vestibulocochlear nerve and
the surface was stained with waterproof ink in different colours to
distinguish between the anterior and posterior hemisphere, the anterior and
posterior part of the vermis, and the flocculonodular lobe. After removing the
flocculonodular lobe, the cerebellum was embedded in 7% agar, and cut in a
systematically random manner into slabs approximately 4 mm thick, using a
cutting machine with a 4 mm interval. Each slab was used to estimate the
volume of the different regions (see below). Starting randomly with either the
first or the second slab, every second slab was cut systematically into 4 mm
wide columns or rods and every nth rod was sampled to provide
approximately five to eight rods from each of the five regions. The regions
from which the rods were taken were identified by their coloured surfaces.
Larger areas of white matter were removed and the rods rotated around their
longitudinal axes and embedded in agar. The number of rods was decided on the
basis of a pilot study (see Andersen et
al, 1992). The flocculonodular lobe, consisting of three
parts, was rotated clockwise, the first part randomly, the other two parts
rotated 90° and 180° to the first, respectively. All were embedded in
7% agar and cut into 2 mm slabs. For more details regarding the vertical axis
principle, see Baddeley et al
(1986), and for further
practical details of the stereological design, see Andersen et al
(1992). The sampled rods were
dehydrated and embedded in glycolmethacrylate for sectioning. From each
three-dimensional uniformly random block, a central section 40 µm thick was
cut parallel to the vertical axis and stained with a modified Giemsa stain. On
the basis of the results of a pilot study, the Giemsa stain was preferred
because it gave a better contrast between cells than the Weil stain used in
our earlier study.
Estimation of total volumes
Estimates of total cell number, N, were obtained by combining an
estimate of the respective reference volumes, V (ref.), using the
Cavalieri method (Gundersen et al,
1988a,b),
and a separately obtained estimate of the three-dimensional numerical density,
NV, for each cell type. The macroscopic volumes were
estimated from:
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To estimate the volume of the granular and molecular layer and the white
matter, the same sections as described below in Surface
estimation were used. Using point counting on the projected images with
a(p)=4 cm2 at a magnification of x 15,
a(p)=1.78 mm2 at tissue level, a simple test grid
was applied to the sections to generate the individual volume fractions
(Vv), where
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The volume of the flocculonodular lobe was estimated using a test grid with a(p)=4 mm2 and t=2.0 mm.
Surface estimation
Using the vertical section design on cerebellum
(Baddeley et al, 1986;
Andersen et al, 1992),
the sampled rods were rotated randomly about their vertical axes. The rods
were then embedded in agar, sectioned longitudinally and stained. On each
section, the vertical axis was identifiable as the long axis of the rod. The
surface area was estimated using a cycloid test system and a projecting
microscope with a final magnification of x 15 (for details, see
Andersen et al, 1992).
The surface (S) was estimated from the following equation:
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Layer thickness
The thickness of the granular layer was estimated using the equation
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Estimation of total cell number
The estimate of total cell number in a region as defined by the equation
below is the product of the volume of each specific layer and the numerical
density of a particular cell type in that layer:
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The Purkinje cells have a large, clear nucleus with one deeply stained nucleolus and irregular Nissl granules. Since a previous study showed that only 1% of the Purkinje cells have more than one nucleolus (Andersen et al, 1992), the nucleolus was used as the counting item. The granular layer is mainly composed of closely packed granule cells in which the nuclei form the major constituent of the cell body. In order to estimate numerical density of the two cell types the optical disector was applied. The optical disector equipment consists of a microscope with a high numerical aperture (1.40) and oil immersion (x 60 or x 100) objectives, which allow focusing on a thin focal plane inside a thick section. A video camera transmits the image to a screen where a counting frame is superimposed using the CAST-GRID PC program (Olympus, Denmark). The microscope stage is driven by a pair of stepping motors with preset steps of known length in the x- and y-directions. A microcator is used to measure stage movements in the z-axis.
A total of 20-30 rods, sampled from the five parts of cerebellum, were used to estimate the numbers of granule and Purkinje cells. For granule cell estimation the x 100 objective was used and the disector height was 10 µm; Purkinje cells were estimated with a x 60 objective and a disector height of 20 µm; the counting frames were 60 µm2 and 25 000 µm2, respectively. One observer performed the counting on coded sections. The interrater reliability had been tested in a pilot study and was below 5%.
Many counting fields contained no Purkinje cell. Therefore, in order to sample at least 50-60 cells, 150-300 disectors had to be sampled at the lowest possible magnification at which the nucleoli were distinguishable. The granular layer was used as a reference volume, which was obtained by using the upper right-hand corner of the counting frame as a reference point. The sampling scheme provided a coefficient of error (CE=s.e.m./mean) of 0.059 for global Purkinje cell estimation in the schizophrenia cerebellar samples and 0.065 for the control samples.
Owing to the uniformity of the granular layer, 100-200 cells counted in about 75-150 disectors in each region were sufficient to give an estimate of global granule cell count with a coefficient of error of 0.047 in the schizophrenia samples and 0.043 in the controls.
Mean volume of Purkinje cells
Each sampled Purkinje cell was measured with a semi-automatic procedure
using the menu-driven computer program, the rotator method
(Jensen & Gundersen,
1993), in which the volume of an arbitrary object can be estimated
by rotating it about an arbitrary axis through a unique point in the object.
The vertical axis is aligned parallel to the y-axis on the screen.
Using the nucleolus as the unique point, the vertical axis is shown on the
monitor by the interactive software. The top and bottom boundary points of the
cell or nucleus are indicated by the operator, and the program systematically
creates uniformly random test lines perpendicular to the vertical axis.
Intersections between the lines and the boundaries are indicated by the
operator and the volume is given in cubic micrometres. The volume of the
perikaryon and cell nucleus was estimated for each sampled Purkinje cell. A
mean of 345 Purkinje cells were counted and their volume estimated for each
cerebellum.
Statistics
Differences between groups were judged by a two-tailed Student's unpaired
t-test employing a significance level of 0.05. The inter-individual
variation, the coefficient of variation (CV=standard deviation/mean), is shown
in parentheses following the group mean values.
The precision of individual estimates is indicated by the coefficient of error, which was 0.02-0.12 in all macroscopic volume estimations. The coefficient of error for estimates of total number of Purkinje cells globally in both schizophrenia and control samples was 0.04-0.06, but was larger in sub-regions, where it varied from 0.16 to 0.25 for Purkinje cells and from 0.03 to 0.17 for the granule cells. The larger values were due partly to the sampling design, but also to the heterogeneous distribution of the cells.
The volume estimates of Purkinje cells were right-skewed and consequently
analysed after logarithmic transformation. Mean values were reported as
geometric means:
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RESULTS |
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No overall statistically significant difference was found between the global mean perikaryon volume of the Purkinje cells in schizophrenia (12 400 µm3, CV=0.24) and controls (13 800 µm3, CV=0.22; P=0.34) nor in the volume of the Purkinje cell nucleus in schizophrenia (1220 µm3, CV=0.22) v. controls (1310 µm3, CV=0.17; P=0.43) (Fig. 1). The mean volumes in the five sub-regions are shown in Table 5. The granular and molecular layer is about 0.4-0.6 mm thick with little variation in the entire cerebellum, except in the flocculonodular lobe, in which it is thinner in both groups (see Table 4).
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No statistically significant correlation was found between the total number of granule cells, the total number of Purkinje cells, or the mean Purkinje cell perikarya and nuclei volumes, and fixation time and medication. However, a statistically significant correlation was found between the post-mortem interval and the total number of granule cells in the schizophrenia group (coefficient of correlation, r=-0.56, P=0.015) but not in the control group. Furthermore, we found a statistically significant correlation between the volume of the Purkinje cell perikarya and the Purkinje cell nuclei, and the cerebellar weight in both groups: schizophrenia group r(perikaryon)=0.80, P=0.018, r(nuclei)=0.78, P=0.02; control group, r(perikaryon)=0.91, P=0.0003, r(nuclei)=0.77, P=0.009. Since the two regression lines did not differ, the analysis is performed on the combined material (Fig. 2).
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Shrinkage
During the preparation of the rods for histological processing, extra rods
were taken to measure shrinkage. The area of the rods was measured before and
after histological processing and compared. In accordance with other studies,
no net shrinkage was detectable
(Pakkenberg et al,
1989; Brændgaard et
al, 1990). A large variation between the brains was observed;
however, no global difference was found between the schizophrenia group and
the control group.
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DISCUSSION |
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Previous studies of the cerebellum
Computed tomography (CT) studies of patients with schizophrenia have
reported a reduction in dorsal vermal volume of 10% or more in patients
compared with controls (for review see
Snider, 1982). Heath et
al (1979) reported
predominantly vermal atrophy in 34 out of 85 patients, and
Lippman et al (1982)
found a 17% smaller vermis in patients compared with controls, and one or more
abnormal dimensions in cerebella in 16 of 54 cases of schizophrenia.
Weinberger et al
(1979), also using CT scans,
found an abnormally small cerebellar vermis in 9 out of 60 cases of
schizophrenia. In all these studies the estimation was made by visual
assessment. Using planimetry in a magnetic resonance imaging (MRI) study,
Nasrallah et al
(1991) reported larger
cerebellar structures in men with schizophrenia compared with controls,
whereas Nopoulos et al
(1999) also using MRI,
but applying automated methods showed no group difference in cases of
schizophrenia compared with controls.
In a non-uniform morphometric study of the anterior cerebellar vermis, Weinberger et al (1980) found that the area of the vermis was smaller in 5 out of 12 cerebella from individuals with schizophrenia than in any of the 7 control subjects. Reyes & Gordon (1981) reported the linear density of Purkinje cells to be decreased in the cerebellar vermis in 8 cases of schizophrenia compared with 12 controls. Stevens (1982), using conventional counting/quantitative methods, reported either gliosis or Purkinje cell loss in a proportion of cerebella from patients with schizophrenia. Tran et al (1998), measuring the cross-sectional area of Purkinje cells using computer-assisted image analysis, reported reduced Purkinje cell size in the superior vermis in elderly patients with schizophrenia, but did not find any differences in linear density between patients and controls.
Clinical data
Kinney et al
(1999) conducted a clinical
study including 54 persons with schizophrenia and 73 of their relatives, 37
persons with bipolar affective disorder, and 24 persons with a history of
substance abuse. The people with schizophrenia and their relatives had a
higher proportion of cerebellar symptoms, especially balance abnormality, than
did the other patients and the control group. Rubin et al
(1994) conducted a study of 44
patients with a first episode of schizophrenia or schizophreniform disorder
(mean age 27.5 years), and a control group of 24. All patients had a full
neurological examination when first admitted to hospital, and were found to
have more neurological abnormalities than the control group, but the only
statistically significant abnormality was seen in cerebellar functions. These
data could indicate cerebellar involvement in schizophrenia, primarily vermal
atrophy.
Cerebellum and cognitive function
Although it is generally recognised that the projection from the cerebellum
reaches the motor areas of the frontal lobe (Brodmann areas 4 and 6), it is
not as widely recognised that the cerebellar projection also reaches some
prefrontal areas (Leiner et al,
1993). Even in the complete absence of any motor activity, the
cerebellum is activated when humans perform certain cognitive and language
tasks. The inferior lateral part of the cerebellum in particular is markedly
activated during both mental counting and mental imagery
(Petersen & Fiez, 1993;
Ryding et al, 1993).
A positron emission tomography study by Andreasen et al
(1996) points to a
dysfunctional prefrontal-thalamocerebellar circuitry in schizophrenia.
Patients with cerebellar abnormalities found post-mortem, such as agenesis or
hypoplasia of the cerebellum, paraneoplastic degeneration and
dentate-rubro-pallido-lusian atrophy, have been described as mentally
abnormal (for review see Katsetos
et al, 1997). Several papers have indicated cerebellar
involvement in autism (Piven et
al, 1992; Courchesne
et al, 1994), and atrophy has been described by
Courchesne et al
(1994), who suggested that
cerebellar maldevelopment contributes to the cognitive and social deficits
characteristic of this disease. The patients' inability to perform rapid
attention shifts between auditory and visual stimuli might be one reason for
their social and cognitive problems.
Evaluation of results
The patients in this study all had severe schizophrenia and had a long
history of neuroleptic treatment (3-30 years). None of the parameters tested
(the total volume of the cerebellum, the total number of granule and Purkinje
cells, the mean volume of Purkinje cells, and the mean numbers of granule and
Purkinje cells in sub-regions of cerebellum) showed any statistically
significant difference between the two groups. However, it should be
emphasised that the two groups are small, and that previous studies reporting
significant differences did not find changes in all cases of
schizophrenia.
We found a significant correlation in both groups between the volume of the Purkinje cells (both perikarya and nuclei) and the weight of the cerebellum. This correlation could be interpreted in several ways: either the volume of the cells increases differentially owing to a number of uncontrolled factors that lead to fluid uptake (such as agonal events, post-mortem changes and fixation), or a biological relationship exists between the volume of cerebellum and the volume of the cells, so individuals with a large cerebellum also have large Purkinje cells. This point needs further clarification in a material with fewer variables.
This study presents estimates of the total number of Purkinje and granule cells in the cerebella of eight individuals with schizophrenia compared with ten controls. No problem was encountered in identifying the different cell types; although a few ectopic granule cells can be found outside the granular layer, they have no impact on the final estimates compared with the total granule cell number.
The result should be considered a rough estimate of the population means of the two groups, since the groups were very small. However, the quantitation provided estimates obtained from methods based on unbiased principles. Our data do not exclude a minor to moderate cell or volume loss, but major volume or cell loss in the cerebellar cortex as proposed by others as a pathogenic factor in schizophrenia seems unlikely. Cerebellar dysfunction caused by undetected morphologic change is still a possibility. For example, the number of synapses or cells in the deep cerebellar nuclei and the number of glial cells were not estimated in this material and their relevance is therefore unknown.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication January 30, 2002. Revision received August 28, 2002. Accepted for publication November 12, 2002.
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