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Reduced Glial Cell Density and Neuronal Size in the Anterior Cingulate Cortex in Major Depressive Disorder
David Cotter, MRCPsych, PhD;
Daniel Mackay, BSc;
Sabine Landau, PhD;
Robert Kerwin, MRCPsych, PhD, DSc;
Ian Everall, MRCPsych, PhD
Arch Gen Psychiatry. 2001;58:545-553.
ABSTRACT
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Background Glial cells are more numerous than neurons in the cortex and are crucial
to neuronal function. There is evidence for reduced neuronal size in schizophrenia,
with suggestive evidence for reduced glial cell density in mood disorders.
In this investigation, we have simultaneously assessed glial cell density
and neuronal density and size in the anterior cingulate cortex in schizophrenia,
major depressive disorder, and bipolar disorder.
Methods We examined tissue from area 24b of the supracallosal anterior cingulate
cortex in 60 postmortem brain specimens from 4 groups of 15 subjects, as follows:
major depressive disorder, schizophrenia, bipolar disorder, and normal controls.
Glial cell density and neuronal size and density were examined in all subjects
using the nucleator and the optical disector.
Results Glial cell density (22%) (P = .004) and neuronal
size (23%) (P = .01) were reduced in layer 6 in major
depressive disorder compared with controls. There was some evidence for reduced
glial density in layer 6 (20%) (P = .02) in schizophrenia
compared with controls, before adjusting for multiple layerwise comparisons,
but there were no significant changes in neuronal size. There was no evidence
for differences in glial density or neuronal size in bipolar disorder compared
with controls. Neuronal density was similar in all groups to that found in
controls.
Conclusion These findings suggest that there is reduced frontal cortical glial
cell density and neuronal size in major depressive disorder.
INTRODUCTION
THERE ARE 3 main types of glial cell populations in the central nervous
system and together they constitute well over half of all cells in the brain.
Until recently, they have been largely viewed as "passive handmaidens" to
neurons, and their central role in cortical and neuronal function has not
been fully appreciated.1 They have important
roles in synaptic function,2, 3, 4
clearance of extracellular ions5 and transmitters,6 neuronal metabolism,7, 8, 9
and neuronal migration.10 There is also some
evidence that cortical glial cell numbers may be increased by neuroleptic
medication in primates,11 that glial cell density
is reduced in the prefrontal cortex,12 and that
the subgenual anterior cingulate cortex (ACC)13
is reduced in major depressive disorder (MDD) and the orbitofrontal14 cortex in schizophrenia. These findings suggest that
glial cell dysfunction may be involved in the pathophysiology of major psychiatric
disorders.
Macroscopic investigations of schizophrenia, bipolar disorder (BPD),
and MDD show many similarities in brain pathology, with the differences being
quantitative rather than qualitative. For example, ventricular dilatation
and reduced hippocampal and cortical volumes are seen in schizophrenia,15 but also to a less marked degree in MDD and BPD.16, 17 These investigations also indicate
which cortical regions are predominantly affected in MDD and schizophrenia.16, 17, 18, 19, 20
In MDD, there is reduced metabolism in the ACC21
on the left side.22, 23, 24
Abnormalities of the prefrontal cortex are also described in schizophrenia,25 and while the ACC is again implicated,26, 27, 28
the changes are neither so marked nor so lateralized as in MDD. The presence
of these ACC abnormalities in MDD and schizophrenia are consistent with the
known functions of this cortical region in information processing, attention,
and in the expression and modulation of emotion.29, 30
As these functions are altered in schizophrenia31
and MDD,19 this area is a candidate region in
which to search for the presence of distinct microscopic neuroanatomical substrates
for these disorders.
Microscopically, investigations of schizophrenia point to abnormalities
of neuronal cytoarchitecture and neuropil,15
with evidence for reduced neuronal size.15, 32
Whether such changes are also present in MDD and BPD is not yet clear, for
there have been few investigations. In MDD, reduced glial density has been
described,12, 13 but this has not
been a consistent finding in schizophrenia.13, 33, 34, 35, 36
It has been proposed that reduced glial cell density may be specific to MDD
and BPD,12 and alternatively, that if reduced
glial cell density is a feature of schizophrenia, then it exhibits a region-specific
distribution.34 In this study, we set out to
characterize neuronal and glial cell density and neuronal size in the ACC
in normal human brain, schizophrenia, BPD, and MDD.
SUBJECTS AND METHODS
SUBJECTS
Human brain specimens from Brodmann area 24 were obtained from the Stanley
Foundation Brain Consortium.37 The sample consisted
of 60 subjects (15 normal controls, 15 subjects with schizophrenia, 15 with
BPD, and 15 with MDD) and is the same as that used previously to investigate
subgenual ACC.13 Diagnoses were made according
to DSM-IV38 criteria.
Detailed case summaries were provided on demographic, clinical, and histological
information (see Table 1 for group
summary details). All brains underwent clinical neuropathological examination
and none demonstrated evidence of neurodegenerative changes or other pathological
lesions. Messenger RNA levels of the housekeeping gene glyceraldehyde phosphate dehydrogenase were measured in the Stanley
Foundation Brain Consortium laboratory by the reverse transcription polymerase
chain reaction and they were excellent to good in all groups, demonstrating
good tissue preservation.
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Table 1. Group Summaries of Demographic, Clinical, and Histological
Information on the Brains Donated by the Stanley Foundation*
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Tissue was available from only 1 hemisphere of each brain, with roughly
equal numbers sampled in a random manner from each side of the brain (Table 1). Hemispheres were fixed in 10%
phosphate-buffered formalin and then cut in coronal sections of roughly 1-cm
thickness. From these slices, a block was taken from the supracallosal ACC
approximately 2-cm caudal to the tip of the genu of the corpus callosum and
processed to paraffin wax. From these blocks, a series of 20 sections of 30-µm
thickness were taken and 5 sections were systematically randomly sampled for
analysis. All sections were then stained with cresyl violet according to standard
methods.
IDENTIFICATION OF CORTICAL LAMINA
For each case, Brodmann area 24b of the ACC was identified and selected
for analysis according to macroscopic and microscopic criteria.39
This region has clear laminar boundaries, making it a particularly suitable
region for the delineation of laminar specific variations in cortical cytoarchitecture.39 Layer 5 is relatively easily divided into distinct
sublayers (layers 5a and 5b), which we assessed separately, in addition to
the remaining 4 layers. The width of each cortical layer was assessed using
an image analysis system (Image-Pro Plus; Media Cybernetics, Baltimore, Md),40 with which we obtained a series of contiguous images
(20 x 25 images) at 20-times objective magnification, from which a single
composite image was formed. The laminar boundaries were identified on this
image and the mean laminar width was calculated. The percentage of total cortical
width contributed by each layer in each group was then calculated (Table 2).
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Table 2. Observed Median Neuronal Sizes in Square Micrometers and Cortical
Height (Expressed as Percentage of Total Cortical Thickness) Within Categories
Defined by Cortical Layer and Patient Group (n = 15 per Group)*
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3-DIMENSIONAL CELL COUNTING AND NEURONAL SIZE ESTIMATES
In this investigation, neurons were identified by the presence of a
cresyl violet–stained cytoplasm, a single nucleolus, and their generally
larger shape and nonspherical outline. Glia were identified by the absence
of stained cytoplasm, the presence of a thicker nuclear membrane, and more
heterogeneous chromatin within the nucleus.
Sections were viewed using a BH2 Olympus microscope (Olympus Optical
Co [UK] Ltd, London, England) with a 100-times (numerical aperture, 1.4) oil-immersion
objective lens, to which was attached a color video camera (TK1280-E; Microinstruments
Ltd, Oxon, England), a z-axis depth gauge (Heidenhain [GB] Ltd, London, England)
(accurate to <1 µm), and an Olympus x- and y-axis movement gauge.
After the mounting and the staining of tissue sections, the thickness of the
tissue sections was assessed. This had reduced from 30 µm to a mean
(SD) of 23.4 (2.8) µm. Consequently, using an optical disector with
a depth of 15 µm, our guard volumes above and below the disector averaged
4.8 µm. Cell-density estimations were made with the aid of image analysis
software (Stereology 2.5; Kinetic Imaging, Liverpool, England) according to
the stereological optical disector method.41
The dimensions of the disector used were 50.5 x 37.5 µm in the
x- and the y-axis, respectively. There was 1 disector per field.
A systematic random sampling strategy was optimized before the investigation,
so that an equal proportion of sampled neurons was obtained from each of the
5 sections used in each case. This involved estimating the number of fields
required to give more than 100 sampled neurons per layer (and sublayers, in
the case of 5a and 5b) per case, and then calculating the required size of
the steps (taken in a sine wave fashion with random start) between fields,
so that the entire region of each cortical layer of Brodmann area 24b in the
tissue section was sampled. An average of 48 fields were counted per layer
per case for neuronal estimations, and 33 fields for glial estimations. A
mean (SD) of 103 (3.2) neurons and 85 (15) glia were counted in each layer
of each case. Values for the coefficient of error of the neuronal and glial
density estimates in the different cortical layers were less than 5% and 6%,
respectively. Neuronal and glial cell densities are expressed as cell per
mm3/103.
The neuronal size of all disector sampled neurons were estimated using
the stereological estimator of number-weighted volume: the nucleator.42 Thus, we calculated the size (expressed in cubic micrometers)
of more than 100 neurons from each individual layer of each subject. As glial
cytoplasm was unstained, glial cell size was not assessed.
STATISTICAL ANALYSIS
Analysis of Neuronal and Glial Cell Densities
The objective of the statistical analysis was to compare within each
cortical layer the neuronal and glial cell densities of the 3 patient groups
(schizophrenia, BPD, and MDD) with the control group. Layerwise density data
(cell counts and sizes of search area) were obtained by combining the 5 sections
and sampled fields per layer. Because of their possibly skewed distributions,
the density data are summarized by their medians (Table 3). A number of subject-specific clinical and demographic
variables with potential to affect cell densities were recorded (these are
listed in Table 1 in italics. To
compare groups using an adequate model, a forward-selection procedure was
employed to identify variables that could be shown empirically to predict
densities. Within each layer, groups were then compared using models that
adjusted for these variables.
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Table 3. Observed Median Neuronal and Glial Densities (Cells per Cubic
Millimeter/103) Within Categories Defined by Brain Hemisphere,
Cortical Layer, and Subject Group (15 per group)*
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In the model selection stage, all layerwise counts were modeled simultaneously,
employing a log-link Poisson model that used the size of the search area as
an offset. A dispersion parameter was introduced to account for spatial clustering
within fields or sections. In addition, a random effect for subject was included
to account for layerwise densities of the same subject being more similar
than densities from different subjects. The factor layer was always included
in the model, since by definition densities vary between cortical layers.
In the stepwise-forward procedure, the P value threshold
for inclusion of a new variable was chosen to be 10%. The random-effects Poisson
models were fitted using the procedure generalized linear mixed model in the
statistical package Genstat 5,43 which employs
the Schall method44 to fit a generalized linear
mixed model.
Having identified empirical predictors, a log-link Poisson model, using
size of search area as an offset and allowing for overdispersion because of
spatial clustering, was fitted to the cell count data in each layer. Density
ratios between each of the 3 psychiatric groups and the control group adjusted
for the empirical predictors were estimated. Since hemisphere was identified
as a predictor of neuronal as well as glial density (see the "Results" section),
we allowed for the density ratios to differ between hemispheres. Accumulated
analysis of deviance,45 using the experimental
method, was employed to test for differences between the patient groups and
the control group. To account for multiple layerwise testing, the P values of the group comparisons can be compared with .05/6 = 0.008
to achieve an experiment-wise type 1 error probability of 5% according to
the Bonferroni correction. This Poisson modelling was again carried out in
Genstat 5.
Analysis of Neuronal Sizes
The objective of the statistical analysis was to compare within each
cortical layer neuronal sizes of the 3 patient groups with the control group.
Size was recorded for each neuron identified, yielding approximately 100 data
points per case and layer (from 5 tissue sections with approximately 10 fields
per section and layer). Because of their positively skewed distributions,
the neuronal size data are summarized by their medians (Table 2) and analyzed on the log-scale, in which empirical distributions
were well approximated by normal distributions. We employed robust SEs when
fitting our regression models. Such inferences are robust against correlations
between repeated observations on the primary sampling units. Here the cases
constituted the (independent) primary sampling units. The analysis of the
neuronal size data was carried out in analogy to the analyses of the density
data. Out of the variables marked with italics in Table 1, empirical predictors were identified using a forward-selection
procedure and group comparisons adjusted for these variables. The robust model
fitting was carried out in Stata 6.45
RESULTS
ANALYSIS OF NEURONAL DENSITIES
Two predictors of neuronal density were identified at the model selection
stage: age of the patient at death (Wald test:  21
= 6, P = .01; estimated increase in neuronal density
per 10 years' survival, 3.4%; 95% confidence interval [CI], 0.67%-6.3%) and
the brain hemisphere from which the sections were taken (Wald test: 21 = 5.5, P = .02; estimated increase
in neuronal density for left hemisphere relative to right hemisphere, 7.5%;
95% CI, 1.2%-14.2%).
Layerwise comparisons between the 3 patient groups and the control group
were adjusted for the effect of age and hemisphere (see Table 3 for observed median neuronal densities within categories
defined by brain hemisphere, cortical layer, and patient group). There was
some evidence that the ratio of neuronal density between the BPD group and
the control group depended on the hemisphere of the brain in layer 1 at the
single test significance level of 5% (F1,51 = 4.31, P = .04). However, this evidence of an interaction disappeared after
adjusting for the 6 layerwise comparisons. None of the other comparisons were
significant, even at the unadjusted level of 5%.
ANALYSIS OF GLIAL CELL DENSITIES
Two predictors of glial density were identified at the model selection
stage; the pH of the tissue (Wald test: 21 = 7.6 P = .006; estimated increase in glial density of 4% per
0.1 increase in pH; 95% CI, 1.6%-6.6%) and the brain hemisphere (Wald test: 21 = 5.1, P = .02; estimated increase
in glial density for left hemisphere relative to right hemisphere, 14%; 95%
CI, 1.8%-27.6%).
Layerwise comparisons between the 3 patient groups and the control group
were adjusted for the effect of pH and hemisphere (see Table 3 for observed median glial densities within categories defined
by brain hemisphere, cortical layer, and patient group). Tests for overall
differences between patient groups and control group as well as their interactions
with hemisphere were carried out (Table 4). Not adjusting for multiple layerwise comparisons, there seemed
to be a significant difference between the schizophrenic and the control group
and between the depressed patients and the control group in layer 6 (Figure 1). In addition, the ratio of glial
density between the depressed group and the control group seemed to depend
on the hemisphere of the brain in layers 1 and 3. However, after adjusting
for the 6 layerwise comparisons, at the experiment-wise 5% level, the only
significant difference was between the depressed group and the control group
in layer 6 (F1,51 = 8.9, P = .004). In
layer 6, the glial density was estimated to be reduced by 22% in depressed
patients compared with controls (uncorrected 95% CI, 7%-35%) (Table 4).
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Table 4. Approximate F Tests and Comparison of Glial Cell Density Between
Patient Groups and the Control Group (n = 15 per Group) From Accumulated Analysis
of Deviance (Experimental Method), and Single 95% Confidence Intervals (CI)
for Glial Cell Density Ratios Between Patient Groups and the Control Group
(Adjusted for pH and Hemisphere)*
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Glia and neurons in layer 6 of the anterior cingulate cortex. Glia
are small, dark, and generally round, with no stained cytoplasm. Neurons are
larger, have a nucleolus visible within the nucleus and Nissl-stained cytoplasm.
C1 to C3, Control subject: male, aged 44 years. B1 to B3, Case with bipolar
disorder: female, aged 48 years. S1 to S3, Case with schizophrenia: male,
aged 44 years. D1 to D3, Case with major depressive disorder: female, aged
52 years. Fewer glial cells are present in major depressive disorder and schizophrenia.
Although not qualitatively obvious, neurons are smaller in major depressive
disorder (Nissl stain; bar, 12 µm).
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ANALYSIS OF NEURONAL SIZE
During the model selection stage, the age of the patient was identified
as a predictor of neuronal size (t test using robust
SEs: t59 = -1.95, P = .05; estimated decrease in neuronal density per 10 years' survival,
4.7%; 95% CI, -0.1% to 9.2%). This finding is in keeping with previous
literature.46
Layerwise comparisons of neuronal size between the 3 patient groups
and the control group were adjusted for the effect of age (see Table 2 for observed median neuronal sizes within categories defined
by cortical layer and patient group). Tests for overall differences between
patient groups and control group were undertaken (Table 5). These show that at the single-test 5% level neuronal size
differed between the depressed patients and controls in layers 5b and 6. These
comparisons do not remain significant after adjusting for multiple layerwise
comparisons. However, the value for comparing depressed patients with controls
in layer 6 of P = .01 is only slightly exceeding
the adjusted significance level of P = .008 and is
interpreted as mild evidence for a difference between these groups, taking
into account the conservative nature of the Bonferroni procedure. In layer
6, the neuronal size was estimated to be reduced by 23% in depressed patients
compared with controls (uncorrected 95% CI, 6%-37%) (Table 5).
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Table 5. Single 95% Confidence Intervals (CI) and t Tests Based on Robust SEs for Comparing Neuronal Size Between Patient
Groups and the Control Group (n = 15 per Group) (Comparisons Are Adjusted
for Age at Death)*
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COMMENT
In this investigation, we have found evidence for reductions in glial
cell density and neuronal size in layer 6 of the ACC in subjects with MDD.
The estimated sizes of these reductions are 22% and 23%, respectively (Table 4 and Table 5). As glia have important metabolic influences on neurons7, 8, 9 and contribute to synaptic
function2, 3, 4 and neurotransmission,6 the findings imply that abnormalities of glial function
may undermine neuronal function and predispose to MDD.
There have been 2 previous stereological investigations in MDD, and
both support our finding of reduced glial cell density in MDD.12, 13
The first study, that of Ongur and colleagues,13
found reduced glial cell density in the subgenual ACC of the same set of brains
as examined in our investigation of supracallosal ACC. The second, by Rajkowska
et al,12 found reduced glial cell density in
the dorsolateral prefrontal cortex and the caudal orbitofrontal cortex. As
in our investigation, these latter changes were most prominent in the deeper
cortical layers and were accompanied by reduced neuronal size. However, there
are some differences between the 3 investigations. First, Rajkowska et al12 found decreased neuronal density in the prefrontal
cortex in MDD, while our study of the ACC and that of Ongur et al13 did not, suggesting a possible region-specific effect.
Second, Ongur et al13 found no reduction in
neuronal size in MDD. This difference may relate to the lack of laminar specific
data in their study and to the fact that subgenual rather supracallosal ACC
was assessed. Ongur et al13 also found reduced
glial cell density to be most prominent in familial MDD and BPD groups, while
we found no evidence for any changes in microscopic neuroanatomy in BPD, and
we refrained from smaller subdivisions of the patient groups according to
family history. Third, the absolute values for neuronal density differ between
the 3 studies. The reasons for these differences are likely to relate to processing
differences between our study, which used paraffin-embedded material, and
the other studies, which used cryosections from fixed tissue13
and celloidin sections,12 respectively.
Our investigation found a trend for an estimated reduced glial cell
density of 20% in layer 6 in schizophrenia (Table 4). While contrasting with some,13
it is in keeping with previous work showing glial cell reductions in the orbitofrontal,47 anterior cingulate,35, 36
and primary motor cortices.36 These reductions
have been moderate,36 with evidence that schizophrenic
subjects with affective symptoms are more likely to show reduced glial cell
density.35 Reductions in the levels of glial
fibrillary acidic protein,48 which labels astrocytes,
and myelin basic protein,49 which labels oligodendroglia
in the anterior frontal cortex in schizophrenia and MDD, have also been demonstrated;
these findings point to the potential cellular basis of the glial cell deficit
described in our study.
We found no change in neuronal density in the ACC in schizophrenia (Table 3). This contrasts with the studies
of Benes and colleagues,35, 36 which
found reduced density of small neurons in layers 2 through 6,35
and reduced density of all neurons in layer 5 of the ACC36
in schizophrenia. These contrasting results may be caused by differences in
the region within the ACC that was assessed; for example, Benes and colleagues35, 36 may have examined perigenual rather
the supracallosal ACC as assessed in our investigation. Additionally, the
smaller size of the sampled fields in our investigation may have affected
our sensitivity to detect changes in the density of the larger neurons. However,
this would not explain the difference in the results regarding smaller neurons;
we used a 100-times oil-immersion lens that maximized our ability to distinguish
glia from small neurons. Similar discrepancies have also been reported regarding
neuronal density in the prefrontal cortex.33, 50
Neuronal size has previously been reported to be reduced in the prefrontal
cortex in schizophrenia,18 but we found no evidence
for this reduction in our study (Table 5).
In our investigation, tissue was available from 1 hemisphere of each
subject; consequently, we were unable to assess true laterality effects within
our subjects. We did find, however, that neuronal and glial cell densities
were increased in the left hemispheres compared with the right hemispheres
(Table 3). This finding may reflect
genetically determined structural asymmetries in the normal brain,51 such as may be responsible for the recently reported
left-lateralized increase in the ACC fissurization in normal subjects.52 We also found a trend for a dependence on hemisphere
of the changes in glial cell density in layers 1 and 3 between controls and
MDD. This finding is consistent with left-lateralized changes reported in
the ACC in MDD in functional neuroimaging investigations.22, 23, 24
There are several methodological advantages of this study. These include
the pragmatic application of stereologically derived methods, the assessment
of all cortical layers, and the presence of 3 psychiatric groups with good
sample size, clinical details, and careful pathological characterization.
There are a number of potential confounding factors. For example, reduced
glial cell density or neuronal size could be secondary to pharmacological
treatments or group differences in tissue pH. In our analysis, we found that
increasing tissue pH was predictive of increasing glial density. Consequently,
we corrected for this potential confounding factor in our analysis. We found
no evidence that pharmacological treatments (neuroleptics, antidepressants,
or mood stabilizers) had predictive effects on cell density or neuronal sizes.
Indeed, the literature that is available indicates that pharmacological treatments
increase rather than decrease their densities. For example, a recent investigation
suggests that chronic exposure to neuroleptics increases glial density in
the prefrontal cortex.11 There is also preliminary
in vitro evidence that antidepressants activate microglia and cause proliferation
of oligodendroglial cells,53 and that lithium
treatment is associated with gliosis.54, 55
Together, these findings suggest that our finding of reduced glial cell density
is unlikely to be a consequence of pharmacological treatments or group differences
in tissue pH.
There are at present no clear biological mechanisms to explain our findings.
However, there may be a clue in the shared neuroanatomy in schizophrenia and
MDD. Reduced hippocampal and cortical volumes,15, 16, 17
neuronal size,12, 32 and dendritic
spine density56 are features of both schizophrenia
and MDD, and we have now shown reduced glial cell density in both disorders.
These similarities suggest that there may be a shared pathophysiological mechanism.
One intriguing possibility is stress-related, glucocorticoid-mediated toxic
effects.57 The consequences of elevated levels
of glucocorticoids58, 59, 60, 61
are consistent with both the macroscopic and microscopic neuroanatomy described
in MDD12, 13, 14, 15, 16, 17
and schizophrenia.15, 17 Elevated
levels of glucocorticoids are known to reduce astrocyte activity and function,62 and reduced levels of the messenger RNA for the glucocorticoid
receptor are reported in the frontal cortex and hippocampus of subjects with
MDD and schizophrenia.63 Consequently, glucocorticoids
may act directly on neurons, or indirectly through glia to undermine neuronal
and cortical function in both disorders.
However, although the etiology of the glial cell loss is not clear,
the consequences of such loss are potentially far-reaching because of the
crucial roles of glial cells in neurotransmission and synaptic function,2, 3, 4 buffering neurochemical
messengers,5 and providing metabolic support
for neurons.7, 8, 9 Furthermore,
glial cells express receptors64 and transporters5 that are implicated in the monoaminergic neurotransmission
abnormalities of MDD65 and schizophrenia.66 With regard to laminar specificity of cellular pathology,
we found that glial cell density and neuronal size were significantly reduced
only in layer.6 The deeper cortical layers receive
noradrenergic afferents from the locus ceruleus,67
which is implicated in the pathology of MDD,68
and they also project via glutamatergic pathways to subcortical structures
involved in the control of motor functions.69
Therefore, our findings of altered layer 6 cytoarchitecture are consistent
with the clinicopathological picture of MDD.
The glial cells sampled in this investigation do not represent a homogeneous
population. They are composed of distinct populations of oligodendrocytes,
microglia, and astrocytes, whose crucial role in cortical function is being
actively reevaluated.1, 2, 3, 4, 5
From our current data, we cannot identify which of these populations are particularly
affected. Future work will be directed at identifying which of the main glial
populations is deficient and whether this deficiency is primary or secondary
to the disease process.
AUTHOR INFORMATION
Accepted for publication December 21, 2000.
Funded by a Clinician Scientist Fellowship from the Medical Research
Council, London, England (Dr Cotter), and a project award from the Theodore
and Vada Stanley Foundation, Bethesda, Md. Postmortem brains were donated
by the Stanley Foundation Brain Bank Consortium, Bethesda, courtesy of Llewellyn
B. Bigelow, MD, Juraj Cervenak, MD, Mary M. Herman, MD, Thomas M. Hyde, MD,
Joel Kleinman, MD, Jose D. Paltan, MD, Robert M. Post, MD, E. Fuller Torrey,
MD, Michael Knable, MD, Maree J. Webster, MD, and Robert Yolken, MD.
From the Division of
Psychological Medicine and Neuropathology, Sections of Experimental
Neuropathology and Psychiatry (Drs Cotter and Everall and Mr Mackay)
and Clinical Neuropharmacology (Dr Kerwin), and the Department of
Biostatistics and Computing (Dr Landau), Institute of Psychiatry,
London, England.
Corresponding author: David R. Cotter, MRCPsych, PhD, Department
of Psychological Medicine and Neuropathology, Institute of Psychiatry, DeCrespigny
Park, London SE5 8AF, England (e-mail:
david.cotter{at}iop.kcl.ac.uk).
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