Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue1.2001:
Meta-Analysis of Thalamic Size in Schizophrenia
Lisa C. Konick and Lee Friedman
Background: This article presents a meta-analysis of
thalamic size reduction in schizophrenia.
Methods: Reviewed studies were based on magnetic
resonance imaging or postmortem material and included
measures of thalamic volume or thalamic area in schizophrenic patients and comparison subjects. Meta-analysis I
was based on absolute thalamic values (not controlled for
overall brain size), and Meta-analysis II evaluated thalamic size adjusted for brain size.
Results: Meta-analysis I included data from 15 studies
(485 schizophrenic subjects and 500 control subjects).
Twelve (80%) of the studies had negative effect sizes,
which is consistent with the hypothesis that thalamic size
is smaller in schizophrenic subjects compared to control
subjects. The composite effect size was 20.29 (p , .0001;
without outliers: 20.41, p , .0001). Meta-analysis II
included data from 11 studies (313 schizophrenic patients
and 434 control subjects). Ten (91%) of the studies had
negative effect sizes. The composite effect size was 20.35
(p , .0001; without outlier: 20.30, p , .0001).
Conclusions: Both meta-analyses indicate a statistically
significant, small-to-moderate effect size for thalamic size
reduction in schizophrenia; however, the effect size for
thalamic size reduction is modest in comparison to that of
other structural abnormalities noted in schizophrenia.
Biol Psychiatry 2001;49:28 –38 © 2001 Society of Biological Psychiatry
Key Words: Thalamus, schizophrenia, meta-analysis
Introduction
T
he role of the thalamus in schizophrenia has been
studied extensively in recent years (for reviews see
Andreasen 1997; Heckers 1997; Jones 1997; Weinberger
1997). The thalamus comprises a complex circuitry between multiple brain regions, including the prefrontal
cortex, basal ganglia, anterior cingulate, cerebellum, and
the sensory, motor, and association regions of the cerebral
cortex. Additionally, as pointed out by Andreasen (1997)
From the Department of Psychiatry, Case Western Reserve University School of
Medicine, Cleveland, Ohio.
Address reprint requests to Lee Friedman, Ph.D., University Hospitals of Cleveland, Department of Psychiatry, Hanna Pavilion, B68, 11100 Euclid Avenue,
Cleveland OH 44106.
Received April 7, 2000; revised June 22, 2000; accepted June 22, 2000.
© 2001 Society of Biological Psychiatry
and Jones (1997), its presumed roles within the brain pose
strong implications for a relationship between thalamic
abnormalities and schizophrenia.
According to several theories, the etiology of schizophrenia is related to a defect in brain circuitry involving
the thalamus (Andreasen 1997; Jones 1997; Weinberger
1997). Andreasen and colleagues have postulated a theory
of “cognitive dysmetria” in which schizophrenia, as a
neurodevelopmental disorder, is caused by a deficit in
prefrontal–thalamic– cerebellar circuitry (Andreasen
1997). Jones (1997) discusses the linkage in the breakdown of “collective” thalamic components to fragmentation of thought processes common in schizophrenia. Weinberger (1997) emphasizes that the thalamus has important
connections with prefrontal and temporolimbic cortices—
two brain areas widely implicated in the pathophysiology
of schizophrenia.
Although some studies have reported statistically significant thalamic size reductions in groups of schizophrenic patients compared to normal control subjects
(Dasari et al 1999; Flaum et al 1995; Frazier et al 1996;
Pakkenberg and Gundersen 1989; Staal et al 1998), most
studies have failed to replicate these findings (Andreasen
et al 1990; Arciniegas et al 1999; Buchsbaum et al 1996;
Corey-Bloom et al 1995; Gur et al 1998; Hazlett et al
1999; Jernigan et al 1991; Lawrie et al 1999; Lesch and
Bogerts 1984; Portas et al 1998; Rosenthal and Bigelow
1972). This pattern of inconsistency suggests that there is
either no effect or that the magnitude of the effect
size—the difference between the means of two groups
divided by their pooled standard deviations—is at best
only moderate.1
Meta-analysis allows for the integration of studies and
enhances statistical power in the estimation of the true
population effect size. It has been used to estimate effect
sizes for a number of structural abnormalities noted in
schizophrenia (Elkis et al 1995; Friedman et al 1992; Hoge
et al 1999; Nelson et al 1998; Raz and Raz 1991; Van
Horn and McManus 1992; Ward et al 1996; Woodruff et
al 1995; Wright et al 2000). Reliable documentation of
thalamic size reductions in schizophrenia would have
significance for the pathophysiology of the disorder and
1
A reviewer suggests a third alternative—that thalamic size reductions are only
found in a subgroup of patients.
0006-3223/01/$20.00
PII S0006-3223(00)00974-4
Thalamic Size in Schizophrenia
suggest avenues for further research in this area. A recent
meta-analysis did attempt to evaluate thalamic size reductions in schizophrenia but included only three studies of
thalamic volume (Wright et al 2000), whereas we have
included 11–15 studies. In this meta-analytic review, we
attempt to determine if the published literature, taken as a
whole, supports a conclusion that there is a reduction in
absolute or relative (to brain size) thalamic size in schizophrenic patients. Because magnetic resonance imaging
(MRI) studies of thalamic volume are generally considered to be the “best” studies (as opposed to MRI studies of
thalamic area or postmortem neuroanatomic studies), data
from such studies is included in the overall estimates and
also presented separately.
Methods and Materials
Sample of Studies
Two meta-analyses were conducted. Meta-analysis I was based
on raw thalamic values unadjusted for brain size (absolute size),
and Meta-analysis II evaluated thalamic values adjusted for brain
size (relative size).
Studies were identified through literature searches of
MEDLINE using the Internet Grateful Med website (http://
igm.nlm.nih.gov) at the National Library of Medicine. The
searches were based on the following medical subject heading
categories: thalamus, schizophrenia. The initial search was conducted in August 1999 and produced more than 190 articles. To
include more recent articles, additional searches were performed
through March 2000. Titles and abstracts were evaluated for
appropriateness for this study. Case reports, review articles, and
letters were culled from the list. Additional articles were identified through the references of relevant studies and review
articles. After a review of the articles, with consideration of the
inclusion and exclusion criteria below, 16 studies were selected
for inclusion in one or both meta-analyses (Meta-analysis I: 15
studies; Meta-analysis II: 11 studies). Selected studies were
published between 1972 and 1999. All studies included in the
meta-analyses were independently reviewed and evaluated by
both authors of this study to obtain consensus on inclusion
criteria and quantifiable data.
Inclusion and Exclusion Criteria for Studies
Studies for the meta-analyses had to measure either thalamic
volume or thalamic area in a group of patients with schizophrenia, and compare these data with a nonpsychiatric and nonneurologic control group. The studies had to be written in the
English language and include sufficient quantitative information
for computation of an effect size (see “Effect Sizes” below). It
was necessary that effect size estimates were not contaminated
by statistically significant differences in age or gender. Analysis
of variance and x2 analyses were conducted on each study that
provided sufficient information to establish that the patient and
comparison groups did not differ significantly in age or gender
distribution. If this was not possible, and the authors indicated
BIOL PSYCHIATRY
2001;49:28 –38
29
that there were no significant differences between groups, we
included the study. Special procedures were necessary for one
study (Flaum et al 1995; see table footnotes). In one study (Gur
et al 1998), the groups differed significantly on age even though
the age difference was less than 3 years. In our judgment, this
difference was not likely to confound comparison of thalamic
size and the study was included in the meta-analysis.
Two excluded studies had insufficient information to calculate
an effect size (Andreasen et al 1994; Gaser et al 1999). In several
cases, data representing the same group of subjects were referenced in multiple publications (Pakkenberg 1990, 1992, 1993;
Pakkenberg and Gundersen 1989); in these cases, the study
containing the most comprehensive, quantitative data were included in the meta-analyses (Pakkenberg and Gundersen 1989).
Two studies (Corey-Bloom et al 1995; Howard et al 1995)
included groups of schizophrenic patients with illness onsets
after 45 years of age. Data from such groups are not included,
because they represent such an unusual and potentially distinctive form of the disorder; however, the early onset (,45 years)
group from the Corey-Bloom et al (1995) study was incorporated
into our analyses.
Effect Sizes
D-STAT software (Johnson 1989) was used for statistical analysis. The effect size employed was the “standardized mean
difference,” which is defined as the difference between the mean
of the schizophrenia group and the mean of the control group,
divided by their pooled SD. The effect sizes were typically
calculated from means and SDs, although F values and t values
were also employed. The standardized mean differences were
corrected for bias due to sample size (a bias found with small
samples) with the outcome expressed as “d” (Hedges and Olkin
1985). The direction of effect size was negative if schizophrenic
patients had smaller thalamic size compared to control subjects.
D-STAT recomputes rough estimates for p values for effects, and
we report these as “Our p value” in the data tables. A weighted
mean effect size was calculated from the d-scores (Hedges and
Olkin 1985). The heterogeneity of effect sizes (Q-statistic) was
also tested (Hedges and Olkin 1985); a significant p value in this
test suggests that a set of studies is not homogenous.
Fixed Effects Model versus a Random Effects
Model
There is a trend toward the use of random effects models in
meta-analyses as opposed to fixed effects models. (For a discussion of the appropriateness of these models, see Hedges [1994],
Hedges and Olkin [1985], and Raudenbush [1994].) In our view,
the fixed effects model is the appropriate model to apply to brain
imaging studies generally, and to thalamic size specifically, in
relation to schizophrenia. This is because, in our conception,
there is one true effect size that describes the differences between
patients with schizophrenia and control subjects on thalamic size.
With this conception, all of the various studies are simply
estimating this one true effect size, with the inevitable sampling
variation and measurement error. A random effects model would
assume that there are multiple true effect sizes, and, in our
estimation, this does not apply in the present case.
30
L.C. Konick and L. Friedman
BIOL PSYCHIATRY
2001;49:28 –38
Publication Bias, Funnel Plots, and Fail-Safe N
The tendency to publish only significant findings or only those
findings in the direction of the hypothesis leads to publication
bias. Publication bias can often be detected graphically through
“funnel plots” (Light and Pillemer 1984), which plot the total
sample size in each study by its effect size. Based on the law of
large numbers, larger studies will be most representative of true
population effects, and smaller samples will be randomly scattered around the central effect size of larger studies, with scatter
increasing as study size decreases. This creates an inverted
funnel appearance. Publication bias is present when the portion
of the funnel surrounding the 0.0 effect size is missing, suggesting that small studies with nonsignificant results have not been
published. This is often referred to as the “file-drawer problem”
(Rosenthal 1979). Orwin (1983) developed a method to determine the number of unpublished studies with null effects (termed
the “fail-safe N”) that would be required to reduce the overall
effect size to a negligible level.
To understand fail-safe N, assume that there are X studies that
are unpublished that have an effect size of 0.0, i.e., absolutely no
effect. Further suppose that we will consider our estimate of the
thalamic effect size, based on published papers, to be trivial if it
is as small as, say, 0.1 (the figure we used in the present
meta-analyses). Fail-safe N tells us how many unpublished
studies with absolutely no effect are required to bring our
computed effect size, based on published studies, down to the
trivial target level. Suppose that the fail-safe N is a huge number,
for example 1000. It is highly unlikely that there are 1000 studies
with no effect that are unpublished, so we don’t have to worry
about our conclusion that there is an important effect. Suppose
that the fail-safe N is 1. Now we are in trouble, because it is quite
likely that there is at least 1 unpublished study with no effect. In
other words, a large fail-safe N means that our meta-analytically
determined effect size based on published studies is not likely to
be threatened by unpublished studies with no effect. Typically,
the fail-safe N is employed heuristically (Orwin 1983).
Moderators of Effect Sizes
The influence of various study characteristics as mediators of
effect size can be assessed with meta-analytic processes comparable to fixed effects analysis of variance or linear regression
(Hedges and Olkin 1985). Several potential moderators of effect
size were coded for further analysis.
Continuous variables:
1. Study Date: earlier studies on a topic often employ lesser
developed methods, with methodology generally becoming more advanced over time. This can result in an
enlarged or reduced effect size. Therefore, study year was
included as a potential predictor of effect size.
2. Percent Male: the percentage of patients that were male
was coded to allow for assessment of gender effects.
3. Age: the age of schizophrenic patients was coded to assess
potential age effects.
Categorical variables:
1. Study Method: most studies employed MRI measures,
whereas others used postmortem measures.
2. Geometry: some studies were based on volumetric measures, and others were based on measurements of thalamic
area.
3. Plane: studies generally employed measurements from
one of three planes— coronal, midsagittal, or axial.
4. Reliability: some studies reported interrater reliability
statistics and others did not.
5. Medication: it is reasonable to hypothesize that patients
who were medicated may differ significantly from neuroleptic-naive patients.
6. Control Type: some studies recruited normal volunteers,
whereas others used a medical sample.
7. Hemisphere: some studies employed measurements based
on the total thalamus, whereas others used only the left or
right thalamic region.
8. Covariate Type: for Meta-analysis II, we compared studies
that controlled for intracranial size with studies that
controlled for brain size.
There was some degree of ambiguity in several cases in assigning a study to one category or another, but we made our best
estimate and include this information in the relevant table.
In some cases, there were less than four studies in a given
category. In these cases, we refrained from formal statistical
analysis owing to poor representation of certain levels of an
effect.
Results
Meta-Analysis I: Absolute Thalamic Size
GENERAL DESCRIPTION OF STUDIES. Data from
485 schizophrenic subjects and 500 normal comparison
subjects contributed to Meta-analysis I, as outlined in
Table 1. The average patient sample size per study was
32.33, compared to an average size of 33.33 in the control
group. With two exceptions (Lesch and Bogerts 1984;
Rosenthal and Bigelow 1972), all studies were conducted
between 1989 and 1999. The average percentage of male
subjects across these studies was 65% for the schizophrenic groups and 59% for control subjects. The mean
age of schizophrenic patients was 34.78, compared to
33.75 in control subjects. With the exception of one study
(Flaum et al 1995), the groups were not statistically
different in the proportion of male subjects, and with one
minor exception noted above (Gur et al 1998), were not
statistically different on age.
Table 2 presents a list of the studies included in this
meta-analysis, with effect sizes and related data extracted
from each study. Of the 15 studies, 12 (80%) had negative
effect sizes, which is consistent with the hypothesis that
thalamic size is smaller in schizophrenic subjects compared to control subjects. Statistical probabilities (p values
or an indication of nonsignificant findings) were reported
in 11 (73%) of the studies. Four (27%) reported statistically significant results supporting the hypothesis, seven
Thalamic Size in Schizophrenia
BIOL PSYCHIATRY
2001;49:28 –38
31
Table 1. List of Studies in Meta-Analysis I—Absolute Thalamic Size
Schizophrenic patients
Authors
Andreasen et al 1990a
Arciniegas et al 1999a
Buchsbaum et al 1996
Dasari et al 1999
Flaum et al 1995a
Frazier et al 1996
Gur et al 1998b
Jernigan et al 1991
Hazlett et al 1999
Lawrie et al 1999
Lesch and Bogerts 1984
Pakkenberg and Gundersen 1989
Portas et al 1998
Rosthenal and Bigelow 1972
Staal et al 1998d
Control subjects
n
% Male
subjects
Mean age
(years)
n
% Male
subjects
Mean age
(years)
54
21
20
20
96
21
96
42
27
20
15
12
15
10
16
N 5 485
66.67
47.62
95.00
75.00
68.75
61.90
52.08
66.67
74.07
75.00
26.67
66.67
100.00
40.00
75.00
65%
33.43
37.15
30.20
14.74
31.80
14.60
30.46
30.00
38.30
20.70
41.66
63.00
37.60
56.00
42.00
Mean 5 34.78
47
27
15
16
84
33
128
24
32
30
11
12
15
10
16
N 5 500
59.57
55.56
80.00
56.25
51.19
66.67
46.88
79.17
78.13
50.00
72.73
50.00
100.00
50.00
75.00
59%
34.43
34.63
27.50
15.59
30.48
14.60
27.60
32.20
41.80
21.10
46.83
62.00
c
50.00
c
Mean 5 33.75
a
Weighted mean age for male and female subjects.
Previously treated and neuroleptic-naive patient groups were combined as a weighted mean.
Data not available.
d
Subject information is based on a “matched” (according to the authors) comparison of 16 control subjects and 16
schizophrenic patients. Therefore, it was assumed that 12 male subjects comprised both groups. Also, according to the authors, the
subjects were “matched” for age, but mean age for the patient sample was not specifically reported. We took the sum (42.0) of
the mean age of onset (20.1) and the mean illness duration (21.9) to represent the mean age of patients in that study.
b
c
(47%) reported nonsignificant findings, and four lacked
statistical data. Thus, a vote-count of statistically significant studies would conclude there was no effect. Twelve
studies were based on MRI and three on postmortem
measures. Four studies employed area measures and the
remaining 11 employed volumetric measures. Special
considerations for particular studies are footnoted in Table
2.
THE COMPOSITE EFFECT SIZE. The composite effect size for all studies in Meta-analysis I was 20.29 (95%
confidence interval [CI]: 20.42 to 20.16; p , .0001);
however, the set of effect sizes in this analysis was
heterogeneous (Q 5 30.24, p 5 .005). Two studies were
considered as outliers. One was a volumetric MRI study
with a large sample size (Gur et al 1998; n 5 224) and an
effect size near zero (0.01). The other was a volumetric
postmortem study with a small sample size (Rosenthal and
Bigelow 1972; n 5 20) and a large positive effect size
(0.75). These outliers were removed to obtain homogeneity (Q 5 18.50, p 5 .10). After removing these outliers,
the composite effect size for the remaining 13 studies was
20.41 (95% CI: 20.56 to 20.26, p , .0001), a moderate
effect size based on Cohen’s nomenclature (Cohen 1988)
The funnel plot for this analysis is presented as Figure 1.
The funnel plot reveals marked variability in effect size
across studies. Such variability is consistent with the small
sample sizes (total N) in most of these studies. There is no
clear evidence for publication bias, as studies with small
N’s were published with quite small positive and negative
effect sizes. The fail-safe N for this study, based on 13
studies after the removal of outliers, was 67.
COMPOSITE EFFECT SIZES FOR MRI VOLUMETRIC
As suggested above, there is a general consensus that MRI volumetric studies provide the best estimates
of thalamic size. An analysis was conducted that included
only such studies (see also Figure 1). The composite effect
size for the eight volumetric MRI studies in this analysis
was 20.22 (95% CI: 20.37 to 20.07; p 5 .0043). This set
of effect sizes was heterogeneous (Q 5 14.62, p 5 .041).
One study (Staal et al 1998) was removed to obtain
homogeneity (Q 5 7.96, p 5 .24). After removal of the
outlier, the composite effect size was 20.18 (95% CI:
20.33 to 20.02; p 5 .024). When this set of “best” studies
(n 5 8) is meta-analytically compared to all other studies
(postmortem area, postmortem volumetric, MRI area, n 5
7) there was a statistical trend for the “best” studies to
have a smaller effect size (p 5 .09, two-tailed). (The
composite effect size for all MRI studies, regardless of
geometry [area or volume] was 20.28, p , .0001.)
STUDIES.
MODERATORS OF EFFECT SIZE. Moderators Not
Formally Analyzed The following coded variables did
not contain sufficient variability to support formal statistical analysis: method (n 5 15 studies, with only three
32
L.C. Konick and L. Friedman
BIOL PSYCHIATRY
2001;49:28 –38
Table 2. Methods and Effect Sizes for Meta-Analysis I—Absolute Thalamic Size
Author
Staal et al 1998b
Pakkenberg and Gundersen 1989d
Dasari et al 1999e
Frazier et al 1996
Lesch and Bogerts 1984
Flaum et al 1995f
Hazlett et al 1999
Buchsbaum et al 1996
Andreasen et al 1990
Arciniegas et al 1999
Jernigan et al 1991
Lawrie et al 1999g
Gur et al 1998h
Portas et al 1998
Rosenthal and Bigelow 1972
Method
Measure
MRI
Neuropathology
MRI
MRI
Neuropathology
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
Neuropathology
Volume
Volume
Area
Area
Volume
Volume
Volume
Area
Area
Volume
Volume
Volume
Volume
Volume
Volume
Volume (cm3)
of thalamusa
(patients/control
subjects)
c
c
c
c
13.02/14.24
11.24/11.89
11.80/12.44
c
c
11.48/11.72
12.02/12.33
12.90/13.00
9.85/9.82
14.26/13.90
12.02/10.82
Sample size
(patients/control
subjects)
Effect
size
Reported
p value
Our
p value
16/16
12/12
20/16
21/33
15/11
96/84
27/32
20/15
54/47
21/27
42/24
20/30
96/128
15/15
10/10
21.19
21.17
20.90
20.78
20.66
20.47
20.38
20.27
20.27
20.22
20.11
20.06
0.01
0.26
0.75
.0050
.0070
.0085
.0070
ns
.0015
.0079
.0101
.0059
.0987
.0019
.1510
.4277
.1844
.4480
.6539
.8440
.9237
.4788
.1024
c
ns
.4200
.1830
c
c
ns
c
ns
ns
MRI, magnetic resonance imaging.
These are based on our calculations of total thalamic size in cm3. In some cases, thalamic size was based on weighted means of males and females.
b
Effect size information is based on a “matched” (according to the authors) comparison of 16 control subjects and 16 schizophrenic patients.
c
Data not available.
d
Data were reported on mediodorsal thalamic nuclei only.
e
Additional information was provided by the authors for calculation of an effect size.
f
To compute an effect size unconfounded by gender, a separate effect size was calculated for male (20.54) and female (20.41) subjects. These effect sizes were then
averaged for an overall effect size.
g
Data were reported separately on the left and right thalamic regions; these data were analyzed separately to provide an effect size for each region, and then averaged
to produce an overall absolute effect size.
h
Absolute effect size integrates both neuroleptic-naive and previously treated patients.
a
based on postmortem measures); reliability (n 5 15; only
three lacked reliability data); control type (n 5 15 studies;
only three were based on a medical sample); hemisphere
(n 5 15 studies; 13 were based on measures of the total
thalamus, one was based on the left hemisphere, and one
was based on the right hemisphere).
size of 39.5 subjects per study. All studies were published
between 1991 and 1999. Male subjects comprised 71% of
the patient samples and 59% of the control samples. The
average age of schizophrenia subjects was 33.15 years
compared to 31.73 years in control subjects. The groups
Moderators Formally Analyzed but Not Statistically
Significant None of the coded variables were significant
predictors of effect size. The following coded variables
were tested, but were not significant: geometry (n 5 15;
volumetric: 11 studies; area: 4 studies; p 5 .12); plane
(n 5 12; coronal: 6 studies; axial: 6 studies; p 5 .21);
medication (n 5 10; medicated patient sample: 6 studies;
partially medicated sample: 4 studies; p 5 .11); study year
(n 5 15, p 5 .10); percent male (n 5 15, p 5 .72); mean
age (n 5 15, p 5 .71).
Meta-Analysis II: Relative Thalamic Size
DESCRIPTION OF THE STUDIES. Table 3 provides a
list of the 11 studies included in Meta-analysis II. Data
from 313 schizophrenic patients and 434 control subjects
contributed to the meta-analysis, with an average patient
sample size of 28.5 subjects and an average control group
Figure 1. Funnel plot for Meta-analysis I, relating effect size to
total sample size. Each solid dot represents the position of a
single magnetic resonance imaging (MRI) volumetric study.
Each diamond represents the position of a single study that
employed either area and/or postmortem measures. The dotted
line reflects the composite effect size before the removal of
outliers. The dashed line reflects the composite effect size after
the removal of outliers.
Thalamic Size in Schizophrenia
BIOL PSYCHIATRY
2001;49:28 –38
33
Table 3. List of Studies in Meta-Analysis II—Relative Thalamic Size
Schizophrenic patients
Author
Arciniegas et al 1999
Buchsbaum et al 1996
Corey-Bloom et al 1995a
Dasari et al 1999
Flaum et al 1995b
Frazier et al 1996
Gur et al 1998c
Jernigan et al 1991
Hazlett et al 1999
Portas et al 1998
Staal et al 1998e
Control subjects
n
% Male
subjects
Mean age
(years)
n
% Male
subjects
Mean age
(years)
21
20
14
20
96
21
21
42
27
15
16
n 5 313
47.62
95.00
71.43
75.00
68.75
61.90
61.90
66.67
74.07
100.00
75.00
71%
37.15
30.20
59.40
14.74
31.80
14.60
28.90
30.00
38.30
37.60
42.00
Mean 5 33.15
27
15
28
16
84
33
128
24
32
15
32
n 5 434
55.56
80.00
46.43
56.25
51.19
66.67
46.88
79.17
78.13
100.00
75.00
59%
34.63
27.50
61.20
15.59
30.48
14.60
27.60
32.20
41.80
d
d
Mean 5 31.73
a
Data based on early-onset (onset before 45 years of age) group only.
Weighted mean age for males and females in control group.
Effect size calculated on neuroleptic-naive patient group only.
d
Data not available.
e
According to Staal et al (1998) the subjects were “matched” for age, but mean age for the patient sample was not specifically
reported. We took the sum (42.0) of the mean age of onset (20.1) and the mean illness duration (21.9) to represent the mean age
of patients in that study.
b
c
did not differ significantly in the proportion of male
subjects and were not statistically different on age.
Effect sizes and related data extracted from each study
for this meta-analysis are presented in Table 4. Ten of the
11 studies (91%) had negative effect sizes, which are
consistent with the hypothesis that thalamic size is smaller
among schizophrenic subjects versus normal control subjects. Statistical probabilities were reported in nine of the
studies. Of these, four (36%) were statistically significant
in support of the hypothesis and five (45%) were reported
as nonsignificant. Once again, a vote-count of statistically
significant studies would conclude that there was no
effect. All were based on MRI measures. Three (27%)
studies employed area measures and the remaining eight
used volumetric measures. Special considerations for particular studies are footnoted in Table 4.
THE COMPOSITE EFFECT SIZE. The composite effect size for all 11 studies included in this analysis was
20.35 (95% CI: 20.51 to 20.20; p , .0001); however,
this set of effect sizes was heterogeneous (Q 5 20.45, p 5
.025). One MRI volumetric study (Staal et al 1998) with a
very large negative effect size (21.23) was removed
before obtaining homogeneity (Q 5 12.94, p 5 .165).
Table 4. Methods and Effect Sizes for Meta-Analysis II—Relative Thalamic Size
Author
Staal et al 1998
Dasari et al 1999a
Corey-Bloom et al 1995b
Frazier et al 1996
Gur et al 1998d
Flaum et al 1995
Hazlett et al 1999
Jernigan et al 1991
Arciniegas et al 1999
Buchsbaum et al 1996e
Portas et al 1998
Method
Measure
Covariate
Sample size
(patients/control
subjects)
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
Volume
Area
Volume
Area
Volume
Volume
Volume
Volume
Volume
Area
Volume
Total brain volume
Intracranial volume
Cranium size
Cerebral volume
Cranial volume
Cranial volume
Brain volume
Intracranial volume
Total brain volume
Whole brain slice area
Intracranial volume
16/32
20/16
14/28
21/33
21/128
96/84
27/32
42/24
21/27
20/15
15/15
Effect size
21.23
20.84
20.66
20.64
20.41
20.39
20.11
20.06
20.04
20.02
0.49
Reported
p value
.0010
.0139
c
.0200
.0800
,.01
ns
ns
.9000
c
ns
Our
p value
.0001
.0157
.0366
.0215
.0130
.0098
.6821
.8005
.8884
.9593
.1887
MRI, magnetic resonance imaging.
a
Additional information was provided by the authors for calculation of an effect size.
b
Data based on early-onset (onset before 45 years of age) group only.
c
Data not available.
d
Relative effect size reflects only neuroleptic-naive patients.
e
Relative data were reported on anterior, middle, and posterior regions of the left and right thalamus; these data were analyzed separately to provide an effect size for
each of the six regions, and then averaged to produce an overall relative effect size.
34
L.C. Konick and L. Friedman
BIOL PSYCHIATRY
2001;49:28 –38
MRI measures); geometry (n 5 11, with only three
employing area measurements); plane (n 5 11, with only
one study employing midsagittal measures and three
employing coronal measures); reliability (n 5 11, all of
which included interrater reliability data); medication (n 5
11, two of which did not include a medicated patient
sample, and three of which were based on a mixed
sample); control type (n 5 11, all of which included
normal volunteers as a control group); hemisphere (n 5
11, all of which were based on measures of total
thalamus).
Figure 2. Funnel plot for Meta-analysis II, relating effect size to
total sample size. Each solid dot represents the position of a
single magnetic resonance imaging (MRI) volumetric study.
Each diamond represents the position of a single study that used
thalamic area rather than thalamic volume. The dotted line
reflects the composite effect size before the removal of an outlier.
The dashed line reflects the composite effect size after the
removal of the outlier.
After this outlier was removed, the composite effect size
for the remaining studies was 20.30, demonstrating a
small to moderate effect. The composite effect size was
significant (95% CI: 20.46 to 20.14; p , .0001). The
fail-safe N, based on ten studies after the removal of the
outlier study, was 40. The funnel plot for this analysis is
presented as Figure 2. Once again, variability in effect size
across studies, probably due to sampling variation from
studies with small samples, is noted.
COMPOSITE EFFECT SIZES FOR VOLUMETRIC AND
A separate analysis was conducted on the
volumetric MRI studies, excluding the three area studies in
Meta-analysis II (see also Figure 2). The composite effect
size in this analysis was 20.32 (95% CI: 20.49 to 20.15;
p , .0001), demonstrating a small to moderate effect size.
This set of effect sizes was heterogeneous (Q 5 16.37,
p 5 .022). One outlier study (Staal et al 1998) was
removed to obtain homogeneity (Q 5 8.13, p 5 .229). The
composite effect size for the remaining seven studies was
20.25 (95% CI: 20.43 to 20.07; p 5 .003). Because all
of the studies in this meta-analysis were based on MRI and
only three employed thalamic area, a formal statistical
comparison between the “best” studies and the others was
not conducted; however, an examination of Figure 2 does
suggest that the MRI area studies were not distinct from
the MRI volumetric studies.
MRI STUDIES.
MODERATORS OF EFFECT SIZE. Moderators Not
Formally Analyzed The following coded variables did
not contain a sufficient amount of variability to be considered for analysis: method (n 5 11 studies, all based on
Moderators Formally Analyzed but Not Statistically
Significant None of the potential modifiers of effect size
were statistically significant. The following variables were
tested but were not significant as predictors of effect size:
study year (n 5 11, p 5 .64); percent male (n 5 11, p 5
.14), mean age (n 5 11, p 5 .78); and covariate type (n 5
5 brain and n 5 6 intracranial, p 5 .82).
Discussion
The main findings of the present meta-analytic review are
that patients with schizophrenia do indeed have smaller
absolute thalamic size and smaller relative (to brain size)
thalamic size than control subjects. The effect sizes for
thalamic size reductions in schizophrenia were small to
moderate in magnitude (absolute size: 20.29 before outlier removal, 20.41 after outlier removal; relative size:
20.35 before outlier removal, 20.30 after outlier removal). Although the effect sizes are not large, the results of
this study provide evidence that patients with schizophrenia have a statistically significant reduction in thalamic
size compared to normal control subjects. Nonetheless,
this conclusion should be tempered by the evidence of
marked variability in effect size across studies. This
variability probably arises from sampling variation due to
small sample sizes in most studies. Although we intended
to evaluate several moderators of effect size, in the final
analysis, there was either insufficient variability or insufficient statistical power to evaluate the influence of most
of the proposed moderators; however, there were no
statistically significant relationships between age or gender and effect size in either meta-analysis.
The study by Gur et al (1998) deserves special comment, because it is such a large study (n 5 224), because
its results are somewhat inconsistent with the results of the
present review, and because it employed a distinctive
design. The study consisted of 3 groups, comparison
subjects (n 5 128), neuroleptic-naive patients (n 5 21),
and previously treated patients (n 5 75). We were not able
to include the large group of previously treated patients
(n 5 75) in Meta-analysis II, owing to insufficient
Thalamic Size in Schizophrenia
BIOL PSYCHIATRY
2001;49:28 –38
35
Table 5. List of Meta-Analytically Determined Effect Sizes of Structural Brain Measures in Schizophrenia
Measure
Ventricular enlargement
Third ventricle enlargement
Relative hippocampal volume—leftd
Relative hippocampal volume—rightd
Relative thalamic volumed
Cortical sulcal enlargement
Whole brain gray matter
Brain size
Brain size
Whole brain white matter
Intracranial size
Number
of studies
53
23
8
8
11
25
6
27
31
5
18
Effect
sizea
0.70
0.66
0.48
0.46
0.35
0.35
0.31
0.26
0.25
0.19
0.18
Direction of effect
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
.
.
,
,
,
.
,
,
,
,
,
normal
normal
normal
normal
normal
normal
normal
normal
normal
normal
normal
Effect size
after removal
of outliers
p
value
0.57
0.58
c
c
0.30
,.0001
,.0001
,.0001
c
c
c
c
c
c
0.31
,.0001
c
c
c
0.16
c
.0012
n Required
to achieve
0.8 powerb
Reference
39
37
86
86
138
102
129
129
198
343
484
Raz and Raz (1991)
Raz and Raz (1991)
Nelson et al (1998)
Nelson et al (1998)
Present study
Raz and Raz (1991)
Wright et al (2000)
Ward et al (1996)
Wright et al (2000)
Wright et al (2000)
Ward et al (1996)
a
These effect sizes are all adjusted for sample size according to Hedges and Olkin (1985). Also, effect sizes are sorted from largest to smallest, based on the effect size
before removal of outliers when applicable.
b
Power calculation is based on the effect size after removal of outliers, when applicable, and assumes alpha 5 0.05 (1-tailed). Also, n is n per group. This is the required
sample size for a single new study to have a 0.8 power.
c
Data not available.
d
These are based on size relative to brain or intracranial size.
information. Had we been able to, it is likely that the
composite effect sizes for Meta-analysis II would be
reduced somewhat but would probably still be statistically
significant with a very low p value. Second, the paper
seems to suggest that thalamic volume may be increased
by medication, because the largest thalamic volumes noted
were in the previously treated group (larger than comparison subjects), and because thalamic volume was positively and statistically significantly correlated with neuroleptic dose. We are not aware of any other data suggesting
an increase in thalamic volume as an effect of antipsychotic medications, although such effects have been noted
for other subcortical structures (Chakos et al 1994). Most
of the studies in the present meta-analyses were based on
medicated patients and, overall, the thalamic volumes in
these patients were reduced, not enlarged. Two other
points about this study are of interest. As noted above, it
was the only study to be included in the final metaanalysis in which there was a statistically significant,
albeit minor, difference in age between the patients and
control subjects (patients slightly older). Furthermore, the
thalamic volumes in the Gur et al (1998) study were
unusually small (Table 2). The mean thalamic volume of
all other studies was 12.4, but the thalamic volume
reported by Gur et al (1998) was 9.8 and was more than
2.5 SD’s below the mean of the other studies. These points
may offer some clue as to why the results are so distinct,
but we are unable to carry the search further.
There was some evidence that the “best” studies, i.e.,
those based on MRI volumetric assessments, produced
smaller effects than other studies when considering only
absolute thalamic size. The contrast between the “best”
studies and the other studies approached statistical significance (p 5 .09). Nonetheless, the composite effect size of
these MRI volumetric studies was statistically significant
and negative (20.18, p , .05). There was no evidence
supporting an important difference between the “best”
studies and the other studies for relative thalamic size.2
In our view, the data on absolute thalamic size is less
interesting than the data on relative thalamic size for the
following reason: It is known that patients with schizophrenia have small brains (Ward et al 1996; effect size
with outliers removed was 20.31). It is likely that thalamic size is highly correlated with brain size. [Indeed,
two of the papers reviewed herein provide the F test for
the brain volume covariate—Dasari et al (1999),
F(1,47) 5 28.9, p 5 .0001; Flaum et al (1995),
F(1,183) 5 51.2, p , .0001.] If thalamic size is correlated
with brain size, and if brain size is reduced in schizophrenia, then, given a large enough sample and sufficiently
small measurement error, one would expect to find reduced absolute thalamic size in this disorder.
The reduction in relative thalamic size cannot be explained as simply a manifestation of reduced brain size (or
reduced intracranial size). The evidence suggests that the
thalamus occupies a smaller proportion of total brain in
patients with schizophrenia than in control subjects; however, the effect size for this effect was moderate to small
(0.35 or 0.30). It is useful to compare this meta-analytic
finding with other meta-analytically determined effect sizes
for brain structural abnormalities in schizophrenia (Table 5).
The effect size for relative thalamic size reduction is smaller
than the effect sizes for ventricular size enlargement and
slightly smaller than the effect sizes for hippocampal size
2
A reviewer suggests that the failure of the “best” or volumetric studies to have
decreased effect size may relate to definitional problems in tracing ventral
thalamic borders and that thick slice “area” studies might avoid this.
36
L.C. Konick and L. Friedman
BIOL PSYCHIATRY
2001;49:28 –38
reduction; however, the effect size for relative thalamic size
reduction is comparable to the effect size for cortical sulcal
enlargement and is larger than the effect size for brain or
intracranial size reduction in schizophrenia.
Is this relative ranking of effect size an index of
“importance”? As a general matter, we believe that effect
size is one of several possible indicators of importance. It
is worth noting that effect size will be influenced by the
reliability of measurement; to the extent that brain measures or diagnoses are unreliable, an effect size will be
underestimated (O’Grady 1982). In the present case, it
seems reasonable to conjecture that measures of small
structures (e.g., hippocampus) are probably less reliable
than measures of large structures (brain volume, intracranial volume) and thus the true effect size in the case of
small structures may be underestimated. Also, the theoretical importance of an effect may have more to do with its
existence, and/or its specificity to schizophrenia, than with
its magnitude (Richardson 1996).
If relative hippocampal size is small and relative thalamic size is small, presumably some other structure (or
structures) of the brain is (are) relatively large in schizophrenic patients. It is known that the ventricles and sulcal
fluid spaces are larger in these patients. Further, the thalamus
is adjacent to the ventricles. Therefore, a smaller thalamus is
consistent with larger ventricles. Indeed, Portas et al (1998)
reported large, and statistically significant, inverse correlations between thalamic size and ventricular size on the left
(r 5 2.65, p 5 .01) and right (r 5 2.61, p 5 .05) in patients
with schizophrenia. Of course, correlation does not prove
causation, but it does raise the possibility that the decrease in
thalamic size in schizophrenia is secondary to an increase in
ventricular size, or vice versa.
In the meta-analysis discussed here, only reports that
utilized conventional measures (area and volume) of
thalamic size were included. Some new studies, based on
completely different forms of analysis, could not be
included, because they do not provide data in the same
form. Nonetheless, such studies are relevant to the question of thalamic size and/or shape in schizophrenia. For
example, Andreasen et al (1994) employed a “boundingbox” registration procedure to create effect-size maps of
regional differences between patients with schizophrenia
and control subjects. These authors reported that the
thalamic size was reduced in schizophrenics; however,
Wolkin et al (1998) did not find thalamic abnormalities
with a similar approach with several more registration
landmarks and scaling factors. Gaser et al (1999) used a
nonlinear deformation approach and did find evidence for
bilateral thalamic volume reductions. Hazlett et al (1999)
reported shape differences in the thalamus of patients with
schizophrenia, i.e., patients had fewer pixels in the left
anterior region of the thalamus.
Of course, the relative size or overall shape of a large
and complex brain structure is a very crude measure and
may have little implication for the function of the thalamus
in a disorder like schizophrenia. Other neuroanatomic
approaches have provided more specific data on reduced
neuronal and glial cell number or density of various
thalamic nuclei (Pakkenberg 1990, 1992). (For a comprehensive review of this topic, see Heckers 1997.) Blennow
et al (1996) reported a remarkable 50% reduction in
synaptic density in the left thalamus of patients with
schizophrenia. A further analysis by this group emphasized a potential reduction in synaptic terminals or presynaptic vesicles (Landen et al 1999; see also Davidsson et
al 1999). Functional studies of the thalamus based on
positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) have produced mixed results
(Heimberg et al 1998; see Hazlett et al 1999 for PET data
and a brief review).
There are a number of interesting studies reporting
statistically significant reductions in thalamic volume
among asymptomatic first- and second-degree relatives of
schizophrenia patients compared to control subjects (Lawrie et al 1999; Seidman et al 1997, 1999; Staal et al 1998).
These findings suggest that the genetic liability to schizophrenia is expressed, in part, as a reduction in thalamic
volume.
Although studies of late-onset cases (onset after 45
years of age) were not included in the formal metaanalyses, it is perhaps worth noting in passing that two
studies that included such patients did not find evidence of
reduced thalamic size (Corey-Bloom et al 1995; Howard
et al 1995). Interestingly, Corey-Bloom et al (1995) found
significantly larger thalamic volumes in late-onset schizophrenic patients compared to early-onset patients. These
findings suggest that those who present with late-onset
schizophrenia do not possess the same thalamic abnormalities as those who develop schizophrenia at a younger,
more typical, age.
In summary, there is convincing evidence for a reduction in thalamic size in schizophrenia; however, the effect
sizes were quite variable across studies, probably reflecting sampling variation from studies with small samples.
The effect size, although highly statistically significant, is
modest in comparison to other structural abnormalities
noted in schizophrenia. Of course, the overall volume of a
brain structure with the size and complexity of the thalamus may be a very crude index of the health or normality
of that structure.
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Lisa C. Konick and Lee Friedman
Background: This article presents a meta-analysis of
thalamic size reduction in schizophrenia.
Methods: Reviewed studies were based on magnetic
resonance imaging or postmortem material and included
measures of thalamic volume or thalamic area in schizophrenic patients and comparison subjects. Meta-analysis I
was based on absolute thalamic values (not controlled for
overall brain size), and Meta-analysis II evaluated thalamic size adjusted for brain size.
Results: Meta-analysis I included data from 15 studies
(485 schizophrenic subjects and 500 control subjects).
Twelve (80%) of the studies had negative effect sizes,
which is consistent with the hypothesis that thalamic size
is smaller in schizophrenic subjects compared to control
subjects. The composite effect size was 20.29 (p , .0001;
without outliers: 20.41, p , .0001). Meta-analysis II
included data from 11 studies (313 schizophrenic patients
and 434 control subjects). Ten (91%) of the studies had
negative effect sizes. The composite effect size was 20.35
(p , .0001; without outlier: 20.30, p , .0001).
Conclusions: Both meta-analyses indicate a statistically
significant, small-to-moderate effect size for thalamic size
reduction in schizophrenia; however, the effect size for
thalamic size reduction is modest in comparison to that of
other structural abnormalities noted in schizophrenia.
Biol Psychiatry 2001;49:28 –38 © 2001 Society of Biological Psychiatry
Key Words: Thalamus, schizophrenia, meta-analysis
Introduction
T
he role of the thalamus in schizophrenia has been
studied extensively in recent years (for reviews see
Andreasen 1997; Heckers 1997; Jones 1997; Weinberger
1997). The thalamus comprises a complex circuitry between multiple brain regions, including the prefrontal
cortex, basal ganglia, anterior cingulate, cerebellum, and
the sensory, motor, and association regions of the cerebral
cortex. Additionally, as pointed out by Andreasen (1997)
From the Department of Psychiatry, Case Western Reserve University School of
Medicine, Cleveland, Ohio.
Address reprint requests to Lee Friedman, Ph.D., University Hospitals of Cleveland, Department of Psychiatry, Hanna Pavilion, B68, 11100 Euclid Avenue,
Cleveland OH 44106.
Received April 7, 2000; revised June 22, 2000; accepted June 22, 2000.
© 2001 Society of Biological Psychiatry
and Jones (1997), its presumed roles within the brain pose
strong implications for a relationship between thalamic
abnormalities and schizophrenia.
According to several theories, the etiology of schizophrenia is related to a defect in brain circuitry involving
the thalamus (Andreasen 1997; Jones 1997; Weinberger
1997). Andreasen and colleagues have postulated a theory
of “cognitive dysmetria” in which schizophrenia, as a
neurodevelopmental disorder, is caused by a deficit in
prefrontal–thalamic– cerebellar circuitry (Andreasen
1997). Jones (1997) discusses the linkage in the breakdown of “collective” thalamic components to fragmentation of thought processes common in schizophrenia. Weinberger (1997) emphasizes that the thalamus has important
connections with prefrontal and temporolimbic cortices—
two brain areas widely implicated in the pathophysiology
of schizophrenia.
Although some studies have reported statistically significant thalamic size reductions in groups of schizophrenic patients compared to normal control subjects
(Dasari et al 1999; Flaum et al 1995; Frazier et al 1996;
Pakkenberg and Gundersen 1989; Staal et al 1998), most
studies have failed to replicate these findings (Andreasen
et al 1990; Arciniegas et al 1999; Buchsbaum et al 1996;
Corey-Bloom et al 1995; Gur et al 1998; Hazlett et al
1999; Jernigan et al 1991; Lawrie et al 1999; Lesch and
Bogerts 1984; Portas et al 1998; Rosenthal and Bigelow
1972). This pattern of inconsistency suggests that there is
either no effect or that the magnitude of the effect
size—the difference between the means of two groups
divided by their pooled standard deviations—is at best
only moderate.1
Meta-analysis allows for the integration of studies and
enhances statistical power in the estimation of the true
population effect size. It has been used to estimate effect
sizes for a number of structural abnormalities noted in
schizophrenia (Elkis et al 1995; Friedman et al 1992; Hoge
et al 1999; Nelson et al 1998; Raz and Raz 1991; Van
Horn and McManus 1992; Ward et al 1996; Woodruff et
al 1995; Wright et al 2000). Reliable documentation of
thalamic size reductions in schizophrenia would have
significance for the pathophysiology of the disorder and
1
A reviewer suggests a third alternative—that thalamic size reductions are only
found in a subgroup of patients.
0006-3223/01/$20.00
PII S0006-3223(00)00974-4
Thalamic Size in Schizophrenia
suggest avenues for further research in this area. A recent
meta-analysis did attempt to evaluate thalamic size reductions in schizophrenia but included only three studies of
thalamic volume (Wright et al 2000), whereas we have
included 11–15 studies. In this meta-analytic review, we
attempt to determine if the published literature, taken as a
whole, supports a conclusion that there is a reduction in
absolute or relative (to brain size) thalamic size in schizophrenic patients. Because magnetic resonance imaging
(MRI) studies of thalamic volume are generally considered to be the “best” studies (as opposed to MRI studies of
thalamic area or postmortem neuroanatomic studies), data
from such studies is included in the overall estimates and
also presented separately.
Methods and Materials
Sample of Studies
Two meta-analyses were conducted. Meta-analysis I was based
on raw thalamic values unadjusted for brain size (absolute size),
and Meta-analysis II evaluated thalamic values adjusted for brain
size (relative size).
Studies were identified through literature searches of
MEDLINE using the Internet Grateful Med website (http://
igm.nlm.nih.gov) at the National Library of Medicine. The
searches were based on the following medical subject heading
categories: thalamus, schizophrenia. The initial search was conducted in August 1999 and produced more than 190 articles. To
include more recent articles, additional searches were performed
through March 2000. Titles and abstracts were evaluated for
appropriateness for this study. Case reports, review articles, and
letters were culled from the list. Additional articles were identified through the references of relevant studies and review
articles. After a review of the articles, with consideration of the
inclusion and exclusion criteria below, 16 studies were selected
for inclusion in one or both meta-analyses (Meta-analysis I: 15
studies; Meta-analysis II: 11 studies). Selected studies were
published between 1972 and 1999. All studies included in the
meta-analyses were independently reviewed and evaluated by
both authors of this study to obtain consensus on inclusion
criteria and quantifiable data.
Inclusion and Exclusion Criteria for Studies
Studies for the meta-analyses had to measure either thalamic
volume or thalamic area in a group of patients with schizophrenia, and compare these data with a nonpsychiatric and nonneurologic control group. The studies had to be written in the
English language and include sufficient quantitative information
for computation of an effect size (see “Effect Sizes” below). It
was necessary that effect size estimates were not contaminated
by statistically significant differences in age or gender. Analysis
of variance and x2 analyses were conducted on each study that
provided sufficient information to establish that the patient and
comparison groups did not differ significantly in age or gender
distribution. If this was not possible, and the authors indicated
BIOL PSYCHIATRY
2001;49:28 –38
29
that there were no significant differences between groups, we
included the study. Special procedures were necessary for one
study (Flaum et al 1995; see table footnotes). In one study (Gur
et al 1998), the groups differed significantly on age even though
the age difference was less than 3 years. In our judgment, this
difference was not likely to confound comparison of thalamic
size and the study was included in the meta-analysis.
Two excluded studies had insufficient information to calculate
an effect size (Andreasen et al 1994; Gaser et al 1999). In several
cases, data representing the same group of subjects were referenced in multiple publications (Pakkenberg 1990, 1992, 1993;
Pakkenberg and Gundersen 1989); in these cases, the study
containing the most comprehensive, quantitative data were included in the meta-analyses (Pakkenberg and Gundersen 1989).
Two studies (Corey-Bloom et al 1995; Howard et al 1995)
included groups of schizophrenic patients with illness onsets
after 45 years of age. Data from such groups are not included,
because they represent such an unusual and potentially distinctive form of the disorder; however, the early onset (,45 years)
group from the Corey-Bloom et al (1995) study was incorporated
into our analyses.
Effect Sizes
D-STAT software (Johnson 1989) was used for statistical analysis. The effect size employed was the “standardized mean
difference,” which is defined as the difference between the mean
of the schizophrenia group and the mean of the control group,
divided by their pooled SD. The effect sizes were typically
calculated from means and SDs, although F values and t values
were also employed. The standardized mean differences were
corrected for bias due to sample size (a bias found with small
samples) with the outcome expressed as “d” (Hedges and Olkin
1985). The direction of effect size was negative if schizophrenic
patients had smaller thalamic size compared to control subjects.
D-STAT recomputes rough estimates for p values for effects, and
we report these as “Our p value” in the data tables. A weighted
mean effect size was calculated from the d-scores (Hedges and
Olkin 1985). The heterogeneity of effect sizes (Q-statistic) was
also tested (Hedges and Olkin 1985); a significant p value in this
test suggests that a set of studies is not homogenous.
Fixed Effects Model versus a Random Effects
Model
There is a trend toward the use of random effects models in
meta-analyses as opposed to fixed effects models. (For a discussion of the appropriateness of these models, see Hedges [1994],
Hedges and Olkin [1985], and Raudenbush [1994].) In our view,
the fixed effects model is the appropriate model to apply to brain
imaging studies generally, and to thalamic size specifically, in
relation to schizophrenia. This is because, in our conception,
there is one true effect size that describes the differences between
patients with schizophrenia and control subjects on thalamic size.
With this conception, all of the various studies are simply
estimating this one true effect size, with the inevitable sampling
variation and measurement error. A random effects model would
assume that there are multiple true effect sizes, and, in our
estimation, this does not apply in the present case.
30
L.C. Konick and L. Friedman
BIOL PSYCHIATRY
2001;49:28 –38
Publication Bias, Funnel Plots, and Fail-Safe N
The tendency to publish only significant findings or only those
findings in the direction of the hypothesis leads to publication
bias. Publication bias can often be detected graphically through
“funnel plots” (Light and Pillemer 1984), which plot the total
sample size in each study by its effect size. Based on the law of
large numbers, larger studies will be most representative of true
population effects, and smaller samples will be randomly scattered around the central effect size of larger studies, with scatter
increasing as study size decreases. This creates an inverted
funnel appearance. Publication bias is present when the portion
of the funnel surrounding the 0.0 effect size is missing, suggesting that small studies with nonsignificant results have not been
published. This is often referred to as the “file-drawer problem”
(Rosenthal 1979). Orwin (1983) developed a method to determine the number of unpublished studies with null effects (termed
the “fail-safe N”) that would be required to reduce the overall
effect size to a negligible level.
To understand fail-safe N, assume that there are X studies that
are unpublished that have an effect size of 0.0, i.e., absolutely no
effect. Further suppose that we will consider our estimate of the
thalamic effect size, based on published papers, to be trivial if it
is as small as, say, 0.1 (the figure we used in the present
meta-analyses). Fail-safe N tells us how many unpublished
studies with absolutely no effect are required to bring our
computed effect size, based on published studies, down to the
trivial target level. Suppose that the fail-safe N is a huge number,
for example 1000. It is highly unlikely that there are 1000 studies
with no effect that are unpublished, so we don’t have to worry
about our conclusion that there is an important effect. Suppose
that the fail-safe N is 1. Now we are in trouble, because it is quite
likely that there is at least 1 unpublished study with no effect. In
other words, a large fail-safe N means that our meta-analytically
determined effect size based on published studies is not likely to
be threatened by unpublished studies with no effect. Typically,
the fail-safe N is employed heuristically (Orwin 1983).
Moderators of Effect Sizes
The influence of various study characteristics as mediators of
effect size can be assessed with meta-analytic processes comparable to fixed effects analysis of variance or linear regression
(Hedges and Olkin 1985). Several potential moderators of effect
size were coded for further analysis.
Continuous variables:
1. Study Date: earlier studies on a topic often employ lesser
developed methods, with methodology generally becoming more advanced over time. This can result in an
enlarged or reduced effect size. Therefore, study year was
included as a potential predictor of effect size.
2. Percent Male: the percentage of patients that were male
was coded to allow for assessment of gender effects.
3. Age: the age of schizophrenic patients was coded to assess
potential age effects.
Categorical variables:
1. Study Method: most studies employed MRI measures,
whereas others used postmortem measures.
2. Geometry: some studies were based on volumetric measures, and others were based on measurements of thalamic
area.
3. Plane: studies generally employed measurements from
one of three planes— coronal, midsagittal, or axial.
4. Reliability: some studies reported interrater reliability
statistics and others did not.
5. Medication: it is reasonable to hypothesize that patients
who were medicated may differ significantly from neuroleptic-naive patients.
6. Control Type: some studies recruited normal volunteers,
whereas others used a medical sample.
7. Hemisphere: some studies employed measurements based
on the total thalamus, whereas others used only the left or
right thalamic region.
8. Covariate Type: for Meta-analysis II, we compared studies
that controlled for intracranial size with studies that
controlled for brain size.
There was some degree of ambiguity in several cases in assigning a study to one category or another, but we made our best
estimate and include this information in the relevant table.
In some cases, there were less than four studies in a given
category. In these cases, we refrained from formal statistical
analysis owing to poor representation of certain levels of an
effect.
Results
Meta-Analysis I: Absolute Thalamic Size
GENERAL DESCRIPTION OF STUDIES. Data from
485 schizophrenic subjects and 500 normal comparison
subjects contributed to Meta-analysis I, as outlined in
Table 1. The average patient sample size per study was
32.33, compared to an average size of 33.33 in the control
group. With two exceptions (Lesch and Bogerts 1984;
Rosenthal and Bigelow 1972), all studies were conducted
between 1989 and 1999. The average percentage of male
subjects across these studies was 65% for the schizophrenic groups and 59% for control subjects. The mean
age of schizophrenic patients was 34.78, compared to
33.75 in control subjects. With the exception of one study
(Flaum et al 1995), the groups were not statistically
different in the proportion of male subjects, and with one
minor exception noted above (Gur et al 1998), were not
statistically different on age.
Table 2 presents a list of the studies included in this
meta-analysis, with effect sizes and related data extracted
from each study. Of the 15 studies, 12 (80%) had negative
effect sizes, which is consistent with the hypothesis that
thalamic size is smaller in schizophrenic subjects compared to control subjects. Statistical probabilities (p values
or an indication of nonsignificant findings) were reported
in 11 (73%) of the studies. Four (27%) reported statistically significant results supporting the hypothesis, seven
Thalamic Size in Schizophrenia
BIOL PSYCHIATRY
2001;49:28 –38
31
Table 1. List of Studies in Meta-Analysis I—Absolute Thalamic Size
Schizophrenic patients
Authors
Andreasen et al 1990a
Arciniegas et al 1999a
Buchsbaum et al 1996
Dasari et al 1999
Flaum et al 1995a
Frazier et al 1996
Gur et al 1998b
Jernigan et al 1991
Hazlett et al 1999
Lawrie et al 1999
Lesch and Bogerts 1984
Pakkenberg and Gundersen 1989
Portas et al 1998
Rosthenal and Bigelow 1972
Staal et al 1998d
Control subjects
n
% Male
subjects
Mean age
(years)
n
% Male
subjects
Mean age
(years)
54
21
20
20
96
21
96
42
27
20
15
12
15
10
16
N 5 485
66.67
47.62
95.00
75.00
68.75
61.90
52.08
66.67
74.07
75.00
26.67
66.67
100.00
40.00
75.00
65%
33.43
37.15
30.20
14.74
31.80
14.60
30.46
30.00
38.30
20.70
41.66
63.00
37.60
56.00
42.00
Mean 5 34.78
47
27
15
16
84
33
128
24
32
30
11
12
15
10
16
N 5 500
59.57
55.56
80.00
56.25
51.19
66.67
46.88
79.17
78.13
50.00
72.73
50.00
100.00
50.00
75.00
59%
34.43
34.63
27.50
15.59
30.48
14.60
27.60
32.20
41.80
21.10
46.83
62.00
c
50.00
c
Mean 5 33.75
a
Weighted mean age for male and female subjects.
Previously treated and neuroleptic-naive patient groups were combined as a weighted mean.
Data not available.
d
Subject information is based on a “matched” (according to the authors) comparison of 16 control subjects and 16
schizophrenic patients. Therefore, it was assumed that 12 male subjects comprised both groups. Also, according to the authors, the
subjects were “matched” for age, but mean age for the patient sample was not specifically reported. We took the sum (42.0) of
the mean age of onset (20.1) and the mean illness duration (21.9) to represent the mean age of patients in that study.
b
c
(47%) reported nonsignificant findings, and four lacked
statistical data. Thus, a vote-count of statistically significant studies would conclude there was no effect. Twelve
studies were based on MRI and three on postmortem
measures. Four studies employed area measures and the
remaining 11 employed volumetric measures. Special
considerations for particular studies are footnoted in Table
2.
THE COMPOSITE EFFECT SIZE. The composite effect size for all studies in Meta-analysis I was 20.29 (95%
confidence interval [CI]: 20.42 to 20.16; p , .0001);
however, the set of effect sizes in this analysis was
heterogeneous (Q 5 30.24, p 5 .005). Two studies were
considered as outliers. One was a volumetric MRI study
with a large sample size (Gur et al 1998; n 5 224) and an
effect size near zero (0.01). The other was a volumetric
postmortem study with a small sample size (Rosenthal and
Bigelow 1972; n 5 20) and a large positive effect size
(0.75). These outliers were removed to obtain homogeneity (Q 5 18.50, p 5 .10). After removing these outliers,
the composite effect size for the remaining 13 studies was
20.41 (95% CI: 20.56 to 20.26, p , .0001), a moderate
effect size based on Cohen’s nomenclature (Cohen 1988)
The funnel plot for this analysis is presented as Figure 1.
The funnel plot reveals marked variability in effect size
across studies. Such variability is consistent with the small
sample sizes (total N) in most of these studies. There is no
clear evidence for publication bias, as studies with small
N’s were published with quite small positive and negative
effect sizes. The fail-safe N for this study, based on 13
studies after the removal of outliers, was 67.
COMPOSITE EFFECT SIZES FOR MRI VOLUMETRIC
As suggested above, there is a general consensus that MRI volumetric studies provide the best estimates
of thalamic size. An analysis was conducted that included
only such studies (see also Figure 1). The composite effect
size for the eight volumetric MRI studies in this analysis
was 20.22 (95% CI: 20.37 to 20.07; p 5 .0043). This set
of effect sizes was heterogeneous (Q 5 14.62, p 5 .041).
One study (Staal et al 1998) was removed to obtain
homogeneity (Q 5 7.96, p 5 .24). After removal of the
outlier, the composite effect size was 20.18 (95% CI:
20.33 to 20.02; p 5 .024). When this set of “best” studies
(n 5 8) is meta-analytically compared to all other studies
(postmortem area, postmortem volumetric, MRI area, n 5
7) there was a statistical trend for the “best” studies to
have a smaller effect size (p 5 .09, two-tailed). (The
composite effect size for all MRI studies, regardless of
geometry [area or volume] was 20.28, p , .0001.)
STUDIES.
MODERATORS OF EFFECT SIZE. Moderators Not
Formally Analyzed The following coded variables did
not contain sufficient variability to support formal statistical analysis: method (n 5 15 studies, with only three
32
L.C. Konick and L. Friedman
BIOL PSYCHIATRY
2001;49:28 –38
Table 2. Methods and Effect Sizes for Meta-Analysis I—Absolute Thalamic Size
Author
Staal et al 1998b
Pakkenberg and Gundersen 1989d
Dasari et al 1999e
Frazier et al 1996
Lesch and Bogerts 1984
Flaum et al 1995f
Hazlett et al 1999
Buchsbaum et al 1996
Andreasen et al 1990
Arciniegas et al 1999
Jernigan et al 1991
Lawrie et al 1999g
Gur et al 1998h
Portas et al 1998
Rosenthal and Bigelow 1972
Method
Measure
MRI
Neuropathology
MRI
MRI
Neuropathology
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
Neuropathology
Volume
Volume
Area
Area
Volume
Volume
Volume
Area
Area
Volume
Volume
Volume
Volume
Volume
Volume
Volume (cm3)
of thalamusa
(patients/control
subjects)
c
c
c
c
13.02/14.24
11.24/11.89
11.80/12.44
c
c
11.48/11.72
12.02/12.33
12.90/13.00
9.85/9.82
14.26/13.90
12.02/10.82
Sample size
(patients/control
subjects)
Effect
size
Reported
p value
Our
p value
16/16
12/12
20/16
21/33
15/11
96/84
27/32
20/15
54/47
21/27
42/24
20/30
96/128
15/15
10/10
21.19
21.17
20.90
20.78
20.66
20.47
20.38
20.27
20.27
20.22
20.11
20.06
0.01
0.26
0.75
.0050
.0070
.0085
.0070
ns
.0015
.0079
.0101
.0059
.0987
.0019
.1510
.4277
.1844
.4480
.6539
.8440
.9237
.4788
.1024
c
ns
.4200
.1830
c
c
ns
c
ns
ns
MRI, magnetic resonance imaging.
These are based on our calculations of total thalamic size in cm3. In some cases, thalamic size was based on weighted means of males and females.
b
Effect size information is based on a “matched” (according to the authors) comparison of 16 control subjects and 16 schizophrenic patients.
c
Data not available.
d
Data were reported on mediodorsal thalamic nuclei only.
e
Additional information was provided by the authors for calculation of an effect size.
f
To compute an effect size unconfounded by gender, a separate effect size was calculated for male (20.54) and female (20.41) subjects. These effect sizes were then
averaged for an overall effect size.
g
Data were reported separately on the left and right thalamic regions; these data were analyzed separately to provide an effect size for each region, and then averaged
to produce an overall absolute effect size.
h
Absolute effect size integrates both neuroleptic-naive and previously treated patients.
a
based on postmortem measures); reliability (n 5 15; only
three lacked reliability data); control type (n 5 15 studies;
only three were based on a medical sample); hemisphere
(n 5 15 studies; 13 were based on measures of the total
thalamus, one was based on the left hemisphere, and one
was based on the right hemisphere).
size of 39.5 subjects per study. All studies were published
between 1991 and 1999. Male subjects comprised 71% of
the patient samples and 59% of the control samples. The
average age of schizophrenia subjects was 33.15 years
compared to 31.73 years in control subjects. The groups
Moderators Formally Analyzed but Not Statistically
Significant None of the coded variables were significant
predictors of effect size. The following coded variables
were tested, but were not significant: geometry (n 5 15;
volumetric: 11 studies; area: 4 studies; p 5 .12); plane
(n 5 12; coronal: 6 studies; axial: 6 studies; p 5 .21);
medication (n 5 10; medicated patient sample: 6 studies;
partially medicated sample: 4 studies; p 5 .11); study year
(n 5 15, p 5 .10); percent male (n 5 15, p 5 .72); mean
age (n 5 15, p 5 .71).
Meta-Analysis II: Relative Thalamic Size
DESCRIPTION OF THE STUDIES. Table 3 provides a
list of the 11 studies included in Meta-analysis II. Data
from 313 schizophrenic patients and 434 control subjects
contributed to the meta-analysis, with an average patient
sample size of 28.5 subjects and an average control group
Figure 1. Funnel plot for Meta-analysis I, relating effect size to
total sample size. Each solid dot represents the position of a
single magnetic resonance imaging (MRI) volumetric study.
Each diamond represents the position of a single study that
employed either area and/or postmortem measures. The dotted
line reflects the composite effect size before the removal of
outliers. The dashed line reflects the composite effect size after
the removal of outliers.
Thalamic Size in Schizophrenia
BIOL PSYCHIATRY
2001;49:28 –38
33
Table 3. List of Studies in Meta-Analysis II—Relative Thalamic Size
Schizophrenic patients
Author
Arciniegas et al 1999
Buchsbaum et al 1996
Corey-Bloom et al 1995a
Dasari et al 1999
Flaum et al 1995b
Frazier et al 1996
Gur et al 1998c
Jernigan et al 1991
Hazlett et al 1999
Portas et al 1998
Staal et al 1998e
Control subjects
n
% Male
subjects
Mean age
(years)
n
% Male
subjects
Mean age
(years)
21
20
14
20
96
21
21
42
27
15
16
n 5 313
47.62
95.00
71.43
75.00
68.75
61.90
61.90
66.67
74.07
100.00
75.00
71%
37.15
30.20
59.40
14.74
31.80
14.60
28.90
30.00
38.30
37.60
42.00
Mean 5 33.15
27
15
28
16
84
33
128
24
32
15
32
n 5 434
55.56
80.00
46.43
56.25
51.19
66.67
46.88
79.17
78.13
100.00
75.00
59%
34.63
27.50
61.20
15.59
30.48
14.60
27.60
32.20
41.80
d
d
Mean 5 31.73
a
Data based on early-onset (onset before 45 years of age) group only.
Weighted mean age for males and females in control group.
Effect size calculated on neuroleptic-naive patient group only.
d
Data not available.
e
According to Staal et al (1998) the subjects were “matched” for age, but mean age for the patient sample was not specifically
reported. We took the sum (42.0) of the mean age of onset (20.1) and the mean illness duration (21.9) to represent the mean age
of patients in that study.
b
c
did not differ significantly in the proportion of male
subjects and were not statistically different on age.
Effect sizes and related data extracted from each study
for this meta-analysis are presented in Table 4. Ten of the
11 studies (91%) had negative effect sizes, which are
consistent with the hypothesis that thalamic size is smaller
among schizophrenic subjects versus normal control subjects. Statistical probabilities were reported in nine of the
studies. Of these, four (36%) were statistically significant
in support of the hypothesis and five (45%) were reported
as nonsignificant. Once again, a vote-count of statistically
significant studies would conclude that there was no
effect. All were based on MRI measures. Three (27%)
studies employed area measures and the remaining eight
used volumetric measures. Special considerations for particular studies are footnoted in Table 4.
THE COMPOSITE EFFECT SIZE. The composite effect size for all 11 studies included in this analysis was
20.35 (95% CI: 20.51 to 20.20; p , .0001); however,
this set of effect sizes was heterogeneous (Q 5 20.45, p 5
.025). One MRI volumetric study (Staal et al 1998) with a
very large negative effect size (21.23) was removed
before obtaining homogeneity (Q 5 12.94, p 5 .165).
Table 4. Methods and Effect Sizes for Meta-Analysis II—Relative Thalamic Size
Author
Staal et al 1998
Dasari et al 1999a
Corey-Bloom et al 1995b
Frazier et al 1996
Gur et al 1998d
Flaum et al 1995
Hazlett et al 1999
Jernigan et al 1991
Arciniegas et al 1999
Buchsbaum et al 1996e
Portas et al 1998
Method
Measure
Covariate
Sample size
(patients/control
subjects)
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
MRI
Volume
Area
Volume
Area
Volume
Volume
Volume
Volume
Volume
Area
Volume
Total brain volume
Intracranial volume
Cranium size
Cerebral volume
Cranial volume
Cranial volume
Brain volume
Intracranial volume
Total brain volume
Whole brain slice area
Intracranial volume
16/32
20/16
14/28
21/33
21/128
96/84
27/32
42/24
21/27
20/15
15/15
Effect size
21.23
20.84
20.66
20.64
20.41
20.39
20.11
20.06
20.04
20.02
0.49
Reported
p value
.0010
.0139
c
.0200
.0800
,.01
ns
ns
.9000
c
ns
Our
p value
.0001
.0157
.0366
.0215
.0130
.0098
.6821
.8005
.8884
.9593
.1887
MRI, magnetic resonance imaging.
a
Additional information was provided by the authors for calculation of an effect size.
b
Data based on early-onset (onset before 45 years of age) group only.
c
Data not available.
d
Relative effect size reflects only neuroleptic-naive patients.
e
Relative data were reported on anterior, middle, and posterior regions of the left and right thalamus; these data were analyzed separately to provide an effect size for
each of the six regions, and then averaged to produce an overall relative effect size.
34
L.C. Konick and L. Friedman
BIOL PSYCHIATRY
2001;49:28 –38
MRI measures); geometry (n 5 11, with only three
employing area measurements); plane (n 5 11, with only
one study employing midsagittal measures and three
employing coronal measures); reliability (n 5 11, all of
which included interrater reliability data); medication (n 5
11, two of which did not include a medicated patient
sample, and three of which were based on a mixed
sample); control type (n 5 11, all of which included
normal volunteers as a control group); hemisphere (n 5
11, all of which were based on measures of total
thalamus).
Figure 2. Funnel plot for Meta-analysis II, relating effect size to
total sample size. Each solid dot represents the position of a
single magnetic resonance imaging (MRI) volumetric study.
Each diamond represents the position of a single study that used
thalamic area rather than thalamic volume. The dotted line
reflects the composite effect size before the removal of an outlier.
The dashed line reflects the composite effect size after the
removal of the outlier.
After this outlier was removed, the composite effect size
for the remaining studies was 20.30, demonstrating a
small to moderate effect. The composite effect size was
significant (95% CI: 20.46 to 20.14; p , .0001). The
fail-safe N, based on ten studies after the removal of the
outlier study, was 40. The funnel plot for this analysis is
presented as Figure 2. Once again, variability in effect size
across studies, probably due to sampling variation from
studies with small samples, is noted.
COMPOSITE EFFECT SIZES FOR VOLUMETRIC AND
A separate analysis was conducted on the
volumetric MRI studies, excluding the three area studies in
Meta-analysis II (see also Figure 2). The composite effect
size in this analysis was 20.32 (95% CI: 20.49 to 20.15;
p , .0001), demonstrating a small to moderate effect size.
This set of effect sizes was heterogeneous (Q 5 16.37,
p 5 .022). One outlier study (Staal et al 1998) was
removed to obtain homogeneity (Q 5 8.13, p 5 .229). The
composite effect size for the remaining seven studies was
20.25 (95% CI: 20.43 to 20.07; p 5 .003). Because all
of the studies in this meta-analysis were based on MRI and
only three employed thalamic area, a formal statistical
comparison between the “best” studies and the others was
not conducted; however, an examination of Figure 2 does
suggest that the MRI area studies were not distinct from
the MRI volumetric studies.
MRI STUDIES.
MODERATORS OF EFFECT SIZE. Moderators Not
Formally Analyzed The following coded variables did
not contain a sufficient amount of variability to be considered for analysis: method (n 5 11 studies, all based on
Moderators Formally Analyzed but Not Statistically
Significant None of the potential modifiers of effect size
were statistically significant. The following variables were
tested but were not significant as predictors of effect size:
study year (n 5 11, p 5 .64); percent male (n 5 11, p 5
.14), mean age (n 5 11, p 5 .78); and covariate type (n 5
5 brain and n 5 6 intracranial, p 5 .82).
Discussion
The main findings of the present meta-analytic review are
that patients with schizophrenia do indeed have smaller
absolute thalamic size and smaller relative (to brain size)
thalamic size than control subjects. The effect sizes for
thalamic size reductions in schizophrenia were small to
moderate in magnitude (absolute size: 20.29 before outlier removal, 20.41 after outlier removal; relative size:
20.35 before outlier removal, 20.30 after outlier removal). Although the effect sizes are not large, the results of
this study provide evidence that patients with schizophrenia have a statistically significant reduction in thalamic
size compared to normal control subjects. Nonetheless,
this conclusion should be tempered by the evidence of
marked variability in effect size across studies. This
variability probably arises from sampling variation due to
small sample sizes in most studies. Although we intended
to evaluate several moderators of effect size, in the final
analysis, there was either insufficient variability or insufficient statistical power to evaluate the influence of most
of the proposed moderators; however, there were no
statistically significant relationships between age or gender and effect size in either meta-analysis.
The study by Gur et al (1998) deserves special comment, because it is such a large study (n 5 224), because
its results are somewhat inconsistent with the results of the
present review, and because it employed a distinctive
design. The study consisted of 3 groups, comparison
subjects (n 5 128), neuroleptic-naive patients (n 5 21),
and previously treated patients (n 5 75). We were not able
to include the large group of previously treated patients
(n 5 75) in Meta-analysis II, owing to insufficient
Thalamic Size in Schizophrenia
BIOL PSYCHIATRY
2001;49:28 –38
35
Table 5. List of Meta-Analytically Determined Effect Sizes of Structural Brain Measures in Schizophrenia
Measure
Ventricular enlargement
Third ventricle enlargement
Relative hippocampal volume—leftd
Relative hippocampal volume—rightd
Relative thalamic volumed
Cortical sulcal enlargement
Whole brain gray matter
Brain size
Brain size
Whole brain white matter
Intracranial size
Number
of studies
53
23
8
8
11
25
6
27
31
5
18
Effect
sizea
0.70
0.66
0.48
0.46
0.35
0.35
0.31
0.26
0.25
0.19
0.18
Direction of effect
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
.
.
,
,
,
.
,
,
,
,
,
normal
normal
normal
normal
normal
normal
normal
normal
normal
normal
normal
Effect size
after removal
of outliers
p
value
0.57
0.58
c
c
0.30
,.0001
,.0001
,.0001
c
c
c
c
c
c
0.31
,.0001
c
c
c
0.16
c
.0012
n Required
to achieve
0.8 powerb
Reference
39
37
86
86
138
102
129
129
198
343
484
Raz and Raz (1991)
Raz and Raz (1991)
Nelson et al (1998)
Nelson et al (1998)
Present study
Raz and Raz (1991)
Wright et al (2000)
Ward et al (1996)
Wright et al (2000)
Wright et al (2000)
Ward et al (1996)
a
These effect sizes are all adjusted for sample size according to Hedges and Olkin (1985). Also, effect sizes are sorted from largest to smallest, based on the effect size
before removal of outliers when applicable.
b
Power calculation is based on the effect size after removal of outliers, when applicable, and assumes alpha 5 0.05 (1-tailed). Also, n is n per group. This is the required
sample size for a single new study to have a 0.8 power.
c
Data not available.
d
These are based on size relative to brain or intracranial size.
information. Had we been able to, it is likely that the
composite effect sizes for Meta-analysis II would be
reduced somewhat but would probably still be statistically
significant with a very low p value. Second, the paper
seems to suggest that thalamic volume may be increased
by medication, because the largest thalamic volumes noted
were in the previously treated group (larger than comparison subjects), and because thalamic volume was positively and statistically significantly correlated with neuroleptic dose. We are not aware of any other data suggesting
an increase in thalamic volume as an effect of antipsychotic medications, although such effects have been noted
for other subcortical structures (Chakos et al 1994). Most
of the studies in the present meta-analyses were based on
medicated patients and, overall, the thalamic volumes in
these patients were reduced, not enlarged. Two other
points about this study are of interest. As noted above, it
was the only study to be included in the final metaanalysis in which there was a statistically significant,
albeit minor, difference in age between the patients and
control subjects (patients slightly older). Furthermore, the
thalamic volumes in the Gur et al (1998) study were
unusually small (Table 2). The mean thalamic volume of
all other studies was 12.4, but the thalamic volume
reported by Gur et al (1998) was 9.8 and was more than
2.5 SD’s below the mean of the other studies. These points
may offer some clue as to why the results are so distinct,
but we are unable to carry the search further.
There was some evidence that the “best” studies, i.e.,
those based on MRI volumetric assessments, produced
smaller effects than other studies when considering only
absolute thalamic size. The contrast between the “best”
studies and the other studies approached statistical significance (p 5 .09). Nonetheless, the composite effect size of
these MRI volumetric studies was statistically significant
and negative (20.18, p , .05). There was no evidence
supporting an important difference between the “best”
studies and the other studies for relative thalamic size.2
In our view, the data on absolute thalamic size is less
interesting than the data on relative thalamic size for the
following reason: It is known that patients with schizophrenia have small brains (Ward et al 1996; effect size
with outliers removed was 20.31). It is likely that thalamic size is highly correlated with brain size. [Indeed,
two of the papers reviewed herein provide the F test for
the brain volume covariate—Dasari et al (1999),
F(1,47) 5 28.9, p 5 .0001; Flaum et al (1995),
F(1,183) 5 51.2, p , .0001.] If thalamic size is correlated
with brain size, and if brain size is reduced in schizophrenia, then, given a large enough sample and sufficiently
small measurement error, one would expect to find reduced absolute thalamic size in this disorder.
The reduction in relative thalamic size cannot be explained as simply a manifestation of reduced brain size (or
reduced intracranial size). The evidence suggests that the
thalamus occupies a smaller proportion of total brain in
patients with schizophrenia than in control subjects; however, the effect size for this effect was moderate to small
(0.35 or 0.30). It is useful to compare this meta-analytic
finding with other meta-analytically determined effect sizes
for brain structural abnormalities in schizophrenia (Table 5).
The effect size for relative thalamic size reduction is smaller
than the effect sizes for ventricular size enlargement and
slightly smaller than the effect sizes for hippocampal size
2
A reviewer suggests that the failure of the “best” or volumetric studies to have
decreased effect size may relate to definitional problems in tracing ventral
thalamic borders and that thick slice “area” studies might avoid this.
36
L.C. Konick and L. Friedman
BIOL PSYCHIATRY
2001;49:28 –38
reduction; however, the effect size for relative thalamic size
reduction is comparable to the effect size for cortical sulcal
enlargement and is larger than the effect size for brain or
intracranial size reduction in schizophrenia.
Is this relative ranking of effect size an index of
“importance”? As a general matter, we believe that effect
size is one of several possible indicators of importance. It
is worth noting that effect size will be influenced by the
reliability of measurement; to the extent that brain measures or diagnoses are unreliable, an effect size will be
underestimated (O’Grady 1982). In the present case, it
seems reasonable to conjecture that measures of small
structures (e.g., hippocampus) are probably less reliable
than measures of large structures (brain volume, intracranial volume) and thus the true effect size in the case of
small structures may be underestimated. Also, the theoretical importance of an effect may have more to do with its
existence, and/or its specificity to schizophrenia, than with
its magnitude (Richardson 1996).
If relative hippocampal size is small and relative thalamic size is small, presumably some other structure (or
structures) of the brain is (are) relatively large in schizophrenic patients. It is known that the ventricles and sulcal
fluid spaces are larger in these patients. Further, the thalamus
is adjacent to the ventricles. Therefore, a smaller thalamus is
consistent with larger ventricles. Indeed, Portas et al (1998)
reported large, and statistically significant, inverse correlations between thalamic size and ventricular size on the left
(r 5 2.65, p 5 .01) and right (r 5 2.61, p 5 .05) in patients
with schizophrenia. Of course, correlation does not prove
causation, but it does raise the possibility that the decrease in
thalamic size in schizophrenia is secondary to an increase in
ventricular size, or vice versa.
In the meta-analysis discussed here, only reports that
utilized conventional measures (area and volume) of
thalamic size were included. Some new studies, based on
completely different forms of analysis, could not be
included, because they do not provide data in the same
form. Nonetheless, such studies are relevant to the question of thalamic size and/or shape in schizophrenia. For
example, Andreasen et al (1994) employed a “boundingbox” registration procedure to create effect-size maps of
regional differences between patients with schizophrenia
and control subjects. These authors reported that the
thalamic size was reduced in schizophrenics; however,
Wolkin et al (1998) did not find thalamic abnormalities
with a similar approach with several more registration
landmarks and scaling factors. Gaser et al (1999) used a
nonlinear deformation approach and did find evidence for
bilateral thalamic volume reductions. Hazlett et al (1999)
reported shape differences in the thalamus of patients with
schizophrenia, i.e., patients had fewer pixels in the left
anterior region of the thalamus.
Of course, the relative size or overall shape of a large
and complex brain structure is a very crude measure and
may have little implication for the function of the thalamus
in a disorder like schizophrenia. Other neuroanatomic
approaches have provided more specific data on reduced
neuronal and glial cell number or density of various
thalamic nuclei (Pakkenberg 1990, 1992). (For a comprehensive review of this topic, see Heckers 1997.) Blennow
et al (1996) reported a remarkable 50% reduction in
synaptic density in the left thalamus of patients with
schizophrenia. A further analysis by this group emphasized a potential reduction in synaptic terminals or presynaptic vesicles (Landen et al 1999; see also Davidsson et
al 1999). Functional studies of the thalamus based on
positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) have produced mixed results
(Heimberg et al 1998; see Hazlett et al 1999 for PET data
and a brief review).
There are a number of interesting studies reporting
statistically significant reductions in thalamic volume
among asymptomatic first- and second-degree relatives of
schizophrenia patients compared to control subjects (Lawrie et al 1999; Seidman et al 1997, 1999; Staal et al 1998).
These findings suggest that the genetic liability to schizophrenia is expressed, in part, as a reduction in thalamic
volume.
Although studies of late-onset cases (onset after 45
years of age) were not included in the formal metaanalyses, it is perhaps worth noting in passing that two
studies that included such patients did not find evidence of
reduced thalamic size (Corey-Bloom et al 1995; Howard
et al 1995). Interestingly, Corey-Bloom et al (1995) found
significantly larger thalamic volumes in late-onset schizophrenic patients compared to early-onset patients. These
findings suggest that those who present with late-onset
schizophrenia do not possess the same thalamic abnormalities as those who develop schizophrenia at a younger,
more typical, age.
In summary, there is convincing evidence for a reduction in thalamic size in schizophrenia; however, the effect
sizes were quite variable across studies, probably reflecting sampling variation from studies with small samples.
The effect size, although highly statistically significant, is
modest in comparison to other structural abnormalities
noted in schizophrenia. Of course, the overall volume of a
brain structure with the size and complexity of the thalamus may be a very crude index of the health or normality
of that structure.
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