+ model
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Psychiatry Research: Neuroimaging xx (2006) xxx – xxx
www.elsevier.com/locate/psychresns
Correlations between clinical symptoms, working memory functions
and structural brain abnormalities in men with schizophrenia
István Szendi a,*, Marianna Kiss b, Mihály Racsmány d,e, Krisztina Boda c,
Csongor Cimmer a, Erika Vörös b, Zoltán A. Kovács a, György Szekeres a,
Gabriella Galsi a, Csaba Pléh d,f, László Csernay b, Zoltán Janka a
a
Department of Psychiatry, University of Szeged, Szeged, Hungary
b
International Medical Center, Szeged, Szeged, Hungary
c
Institute of Medical Informatics, University of Szeged, Szeged, Hungary
d
Research Group on Neuropsychology and Psycholinguistics, Hungarian Academy of Sciences — Budapest University of Technology and
Economics, Budapest, Hungary
e
Department of Psychology, University of Szeged, Szeged, Hungary
f
Department of Cognitive Science, Budapest University of Technology and Economics, Budapest, Hungary
Received 15 October 2004; received in revised form 15 May 2005; accepted 25 May 2005
Abstract
Thirteen male patients with schizophrenia and thirteen male normal control subjects were compared by magnetic resonance
imaging (MRI) on volumes of the straight gyrus (SG), anterior cingulate gyrus, middle frontal gyrus, hippocampus, third ventricle,
cavum septi pellucidi, total brain volume and intracranial volume. In addition, neuropsychological tasks were used to measure
working memory and executive functions. Healthy volunteers and schizophrenic patients showed no significant differences in
mean values for volumes of regions of interests. In the case of the SG, we found a significant difference in laterality: the tendency
toward left dominance in healthy volunteers changed to significant right dominance in patients. The schizophrenic patients showed
lower performance in working memory tasks, and strongly significant group differences were observed in measures of neurological
signs assessed by the Neurological Evaluation Scale (NES). Negative symptoms correlated with the level of spatial working
memory and executive functions. Negative symptoms also correlated with the volume of the right hippocampus, while the rate of
anhedonia negatively correlated with the relative volume of the left SG.
D 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Schizophrenia; Working memory; Executive functions; MRI; Straight gyrus
1. Introduction
The brain structural changes correlating with mental
disorders are usually subtle ones and are not easily
* Corresponding author. 6 Semmelweis str., 6725 Szeged, Hungary.
Tel.: +36 62 545 942; +36 62 545 358; fax: +36 62 545 973.
E-mail address: szendi@nepsy.szote.u-szeged.hu (I. Szendi).
revealed with macroscopic volumetric analyses. Schizophrenia is in part a neurodevelopmental disorder based
on multifocal brain structure changes with a background of defective neuronal migration, myelinisation
and/or cortico–cortico wiring. As a consequence, this
disorder is characterised by defective cytoarchitectonic
and neurochemical connections within and between
certain neuronal networks. Many neocortical areas
0925-4927/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.pscychresns.2005.05.014
PSYN-09170; No of Pages 9
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are affected in schizophrenia, principally structures
within the prefrontal and medial paralimbic regions.
Recent imaging studies revealed changes in the middle
frontal gyrus, the anterior cingulate gyrus, the paracingulate gyrus, and the insula as well as in the
frontomedial and orbitofrontal cortical areas (Goldstein et al., 1999). An alteration of the superior temporal gyrus (STG) was also found, more specifically
of the planum temporale, supramarginal gyrus and
Heschl’s gyrus (Hirayasu et al., 2000). Among subcortical areas, the impairment of the amygdala–hippocampus complex (Wright et al., 2000) and of the
thalamus (Konik and Friedman, 2001) was primarily
detected. A significant rightNleft asymmetry was
found in certain areas such as the STG, in which
leftNright difference is typical among healthy subjects,
and also in the amygdala–hippocampus complex
(Petty, 1999; Sommer et al., 2001). Among developmental anomalies, midline deviations are typical in
schizophrenia. The dilatation of the third ventricle
and the cavum septi pellucidi (CSP) has also been
found to be characteristic (McCarley et al., 1999). In
cases with childhood onset, changes are apparent before the onset of psychosis (James et al., 2002).
There has been a continuous development in the
methods of topographical mapping of in vivo magnetic
resonance imaging (MRI) data in the past decade. A
valuable parcellation method has recently been developed by Crespo-Facorro et al. (2000). Crespo-Facorro
et al. (2000) realised that landmarks cannot always be
identified on each slice as a result of individual variations; therefore they suggested a method by which the
continuity of target regions is captured on consecutive
slices. They divided the neocortex into 41 regions.
Their procedure unites the advantages of the two-dimensional definition of regions in three orthogonal
planes (coronal, sagittal and transaxial) and of the
simultaneous visualization of the three-dimensional reconstruction of the brain. In the present study, we
applied the method of Crespo-Facorro et al. (2000)
(see also Kim et al., 2000), and we used the method
of a French research group for the volumetric measures
of the hippocampus (Duvernoy, 1998).
One of the most influential general models of human
cognition is the working memory model, which postulates that short-term memory operates as a working
space holding information on-line during comprehension, learning and goal-directed behaviour. The tripartite model of working memory assumes that besides a
central executive control system, limited capacity verbal and visuo-spatial subsystems contribute separately
to the temporary maintenance and manipulation of
verbal and visuo-spatial information (Baddeley, 1986;
Baddeley et al., 1998; Baddeley and Logie, 1999).
Although a wide range of cognitive functions is
impaired in schizophrenia, working memory research
has been a prominent area of cognitive neuropsychiatric
research of the syndrome. A number of recent studies
have found that different components of the working
memory system are impaired at different levels in
schizophrenia, and the severity of impairment correlates
with negative and positive symptoms of the illness (for
review, see Keefe, 2000). However, the picture is far
from clear, partly because of the cognitive heterogeneity of experimental tasks and partly because of the
clinical heterogeneity of schizophrenic patient groups
(Bressi et al., 1996; Carter et al., 1996; for a review, see
Palmer and Heaton, 2000).
The most studied aspect of working memory in
schizophrenia is the central executive component. Several lines of research explored the abilities of planning,
flexible strategy changing, fluency and inhibition using
a wide range of neuropsychological tasks that are usually regarded as screening methods for frontal pathology. A number of studies found significant correlations
between clinical symptoms of schizophrenia and working memory functions (see Addington, 2000; Phillips
and David, 2000). For instance, Carter et al. (1996)
found a strong correlation between spatial working
memory capacity and scores on the Scale for the Assessment of Negative Symptoms (Andreasen, 1982). A
strong relationship was found between spatial working
memory and executive functions and positive symptoms such as thought intrusion, delusion and hallucination (Carter et al., 1996; Bressi et al., 1996). Taking all
of these results into consideration, it would be important to clarify the role of working memory subsystems
in the development of schizophrenic symptoms and
also to identify the brain regions underlying these
functional deficits.
In the present study, brain morphology and the
clinical and cognitive performances of male schizophrenic patients treated at the psychiatric outpatient
clinic of the University of Szeged were investigated.
The questions of this preliminary report were whether
specific volumetric changes could be observed in
schizophrenia in areas thought to be involved in working memory and, in addition, whether the brain size
changes would correlate with changes in cognitive
functions and with symptomatology.
All patients were in the early phase of the illness, in
an interepisodic state and under medical treatment. We
measured the intracranial volume, the volume of the
whole brain, the external cerebrospinal fluid space, the
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third ventricle, both hippocampi, both middle frontal
gyri, both anterior cingulate gyri, both straight gyri and
the grey matter of the orbitofrontal cortex. With cognitive tests the functioning of verbal and visuo-spatial
working memory and the abilities of planning and
flexible strategy shifting were assessed.
2. Methods
2.1. Subjects
Only male subjects participated in the experiment,
as we enrolled a relatively low number of subjects in
this research and we wanted to exclude the variance of
brain size attributable to gender differences. Thirteen
patients were selected from the outpatient clinic of the
Department of Psychiatry, University of Szeged. All
patients had a diagnosis of schizophrenia defined by
DSM-IV (American Psychiatric Association, 1994) and
ICD-10 criteria for research (World Health Organization, 1993). All patients were in a stable interepisodic
state, during the early stages of the illness, and under
antipsychotic medication. The 13 normal control subjects were recruited from hospital staff and community
volunteers. They were evaluated with a modified structured interview (Mini International Neuropsychiatric
Interview (MINI) — Hungarian version, Balázs et al.,
2001), and we excluded normal control subjects with a
family history of psychotic and affective spectrum
disorders. All subjects were 25 to 37 years of age,
had scores above 85 in full scale IQ (WAIS, Hungarian
version, Kun and Szegedi, 1997), had a minimum of
8 years of education (primary school), and were able
to give informed consent. Subjects were excluded if
they had a lifetime history of neurological illness, any
medical illness known to affect brain structure, head
injury with loss of consciousness for more than 10
min, psychoactive substance abuse within the last 6
months, or any medical illness that could significantly
constrain neurocognitive functions. Patients were excluded if they had previously undergone electroconvulsive therapy.
The demographic and clinical characteristics of the
subjects are shown in Table 1. Although there was a
significant difference between the groups in education
and IQ measured by the WAIS, the average of the
schizophrenic group was above 100, and the minimum
score was 86. All patients comprehended and carried
out all instructions. There was no difference between
groups in handedness, every subject enrolled in the
study was right-handed judged by the Neurological
Evaluation Scale (NES). Because of the low subject
Table 1
Demographic and clinical characteristics of the subjects
Age (years)
Education (years)
Full scale IQ
Age at onset (years)
Duration of illness (years)
Relapses
PANSS
Positive
Negative
Global
Total
SANS
Affective
Alogia
Avolition
Anhedonia
Attention
SAS
BAS
AIMS
NES
Sensory integration
Motor coordination
Motor sequencing
Global
SDS
Deficit syndrome
Non-deficit
Control
Schizophrenia
(N = 13)
(N = 13)
29.3 F 4.7
14.4 F 2.6
124.3 F 12.7
25.9 F 5.4
11.1 F1.9
101.1 F12.3
21.9 F 4.8
3.9 F 3.0
3.2 F 2.1
Pa
0.139
0.004
0.002
9.9 F 3.8
14.0 F 5.8
27.0 F 9.0
50.9 F 15.3
1.2 F 1.1
1.2 F 1.1
0.9 F 1.0
1.6 F 1.2
0.9 F 1.1
2.5 F 2.3
0.2 F 0.6
0.2 F 0.4
0.1 F 0.3
0.1 F 0.3
0.3 F 0.5
3.6 F 2.6
4.1 F 2.1
1.0 F 1.0
4.9 F 2.6
19.5 F 3.9
0.000
0.026
0.000
0.000
2 patients
11 patients
Values represent mean F S.D.
a
Mann–Whitney U-test.
number we did not consider the effect of antipsychotics. Three of the patients were treated with conventional neuroleptics, six of them with atypical antipsychotics, and four persons with combination of an
atypical oral and a conventional depot injectable neuroleptics. All substances were prescribed in medium
dose according to their medication protocol. No one of
the patients had any known family history of psychotic disorders.
2.2. Clinical tests
Clinical symptoms were assessed by psychiatrists
using the Positive and Negative Syndrome Scale
(PANSS) (Kay et al., 1991), the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen,
1982), the Schedule for the Deficit Syndrome (SDS)
(Kirkpatrick et al., 1989), the Neurological Evaluation
Scale (NES) (Buchanan and Heinrichs, 1989), the
Simpson–Angus Scale (SAS) (Simpson and Angus,
1970), the Abnormal Involuntary Movement Scale
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(AIMS) (Guy, 1976), and the Barnes Akathisia Rating
Scale (BAS) (Barnes, 1989), with assessment of the
demographic and epidemiologic data at the time of the
MRI study.
interest (ROIs) for tracing, and the third step was to
trace by hand in each ROI the surface area or grey
matter on the appropriate coronal and axial slices. After
manual tracing, the volume of the ROI was calculated
by means of the bvolume analysisQ program.
2.3. Working memory tasks
2.4.1. Guidelines of the tracing
Widely used neuropsychological tasks were
employed to measure working memory and executive
functions. The cognitive functions were assessed by
psychiatrists, a trained research assistant and a trained
undergraduate psychology student. We measured verbal
working memory capacity with the Digit Span Forward
and Backward tasks (Wechsler, 1981; Kun and Szegedi,
1997), and the Hungarian version of the Nonword
Repetition Test (Gathercole et al., 1994; Racsmány et
al., 2002). We used the Corsi Blocks (Milner, 1971) and
Visual Patterns Test (Della Sala et al., 1997) for measurement of visuo-spatial working memory capacity.
We assessed executive functions with the Wisconsin
Card Sorting Test (WCST) (Berg, 1948), the Tower
of Hanoi (Simon, 1975), Letter Fluency (Benton and
Hamsher, 1976), and the Category Fluency task (Spreen
and Strauss, 1991).
2.4. MRI scans
All the multimodal MRI examinations were performed on a Signa Horizon 1 Tesla MR Unit (General
Electric, GE) at the International Medical Center
(Szeged, Hungary). Three-dimensional T1 weighted
images using the spoiled gradient echo (SPGR) sequence were obtained in the coronal plane with the
following parameters: echo time (TE) = 3 fr/ms, repetition time (TR) = 33 ms, number of excitations (NEX) = 1,
rotation angle = 458, field of view (FOV) = 24 18,
slice thickness = 1.5 mm, and acquisition matrix of
256 192. Two-dimensional FSE (fast spin echo) T2
sequences were gained as follows: echo time (TE) = 91.1
fr/ms, repetition time (TR) = 4300 ms, number of excitations (NEX) = 3, field of view (FOV)=25 19, acquisition matrix: 384 192. The in plane resolution was
1016 1016 mm in all three planes. MRI data were
postprocessed on an Advantage Windows (Silicon Graphics) workstation with Advantage 3.1 software (developed by GE).
Single manual measurement with intra-rater control
and inter-rater supervision was performed on serial
coronal or axial slices of all regions of interest. The
initial step was the identification of the reference anatomical landmarks that served as boundaries on each
plane. The second step was to determine the regions of
1. Straight gyrus (SG). On each axial slice the SG is
defined as the portion of the frontal lobe along the
olfactory sulcus (OS) medially. The boundary of the
SG on the medial wall is defined by an imaginary
line parallel to the line running through the depth of
the OS. This represents a medial boundary of the
SG. An orthogonal line is traced from the anterior
end of the OS to the medial surface of the hemisphere. The posterior margin of the SG is the suborbital sulcus (SOS).
2. Anterior cingulate gyrus (ACG). The ACG is traced
on serial coronal slices. The most anterior coronal
slice is selected as the one in which the cingulate
sulcus is clearly visualized. The deepest point of the
callosal sulcus and the most medial point of the
dorsal bank of the cingulate gyrus constitute the
inner and the outer boundaries of the ACG. The
posterior margin is determined by the meeting of
the inner and outer boundaries.
3. Orbitofrontal cortex (OFC). The OFC is traced in the
coronal plane. The deepest point of the lateral orbital
sulcus constitutes the lateral boundary of the OFC.
The lateral boundary changes to the frontomarginal
sulcus (FMS) when the lateral orbital sulcus disappears. At the posterior aspect, the orbitoinsular sulcus
(OIS) defines the lateral boundary of the cortex when
the lateral orbital sulcus disappears. The deepest point
of the olfactory sulcus (OS) constitutes the medial
boundary of the OFC on the posterior and intermediate portions of the OFC. On the anterior portion, when
the OS disappears, the deepest point of the superior
rostral sulcus represents the medial boundary of the
OFC.
4. Middle frontal gyrus (MFG). On each coronal slice
the deepest points of the superior frontal sulcus
(SFS) and the inferior frontal sulcus (IFS) constitute
the superior and inferior boundaries of the MFG.
The MFG is usually defined after tracing the SFS
and the IFS. On transaxial slices an imaginery coronal plane (passing through the most anterior tip of
the inner surface of the genu of the corpus callosum)
constitutes the anterior border, and the deepest points
of the precentral sulcus and the SFS constitute the
posterior and the anterior borders.
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5. Third ventricle. It is traced on coronal and transaxial
planes. The third ventricle is formed from its dorsal
to basal epithalamus, thalamus, and hypothalamus.
The lamina terminalis forms the rostral boundary of
the third ventricle. In the area near the hypothalamic
sulcus, a groove for the anterior commissure can be
found. Near the hypothalamus, two additional diverticula can be seen: the optic recess leading toward
the optic chiasm and the infundibular recess directed
toward the pituitary stalk. The suprapineal recess is a
diverticulum above the pineal gland. A few millimeters below the suprapineal recess is a niche, the
pineal recess.
6. Cavum septi pellucidi. It is a cavity between the
frontal horns of the lateral ventricle. It is traced on
the axial plane.
7. Hippocampus. It is traced on the coronal and transaxial planes. The hippocampus can be divided into
three parts: an anterior part or head (a), a middle part
or body (b), and a posterior part or tail (c).
a. The hippocampus head includes an intraventricular part, the hippocampal digitations and an extraventricular or uncal part. The hippocampal
digitations and amygdala are often joined together
across the ventricular cavity. Anterior to the hippocampus, the ventricular cavity often extends
into the deep part of the uncus, as the uncal
process. The uncus, or anterior segment of the
parahippocampal gyrus, curls posteriorly to rest
on the parahippocampal gyrus itself, separated
from the latter by the uncal sulcus.
b. The body includes the intraventricular or deep part
and the extraventricular or superficial part. The
intraventricular part is an element of the floor in
the lateral ventricle. The intraventricular part is
limited to the dentate gyrus, the fimbria and the
hippocampal sulcus. The superficial part of dentate gyrus is the margo denticulatus.
c. The intraventricular part of the hippocampus tail is
flanked medially by the fimbria and laterally by the
collateral trigone. The extraventricular part may be
divided into initial, middle and terminal segments.
8. Supratentorial CSF space. The volume is measured
between the internal lamina and the surface of the
cerebrum.
2.5. Statistical analysis
A Mann–Whitney U-test was used to examine group
differences on demographic, brain structural, cognitive
and clinical variables. Pearson’s product-moment correlations tested relationships between variables. The
measures of laterality of ROI volumes were subjected
to two-way repeated measures analysis of variance
(ANOVA). The level of significance was P = 0.05 in
all cases. In our preliminary report we present the
uncorrected P-values.
3. Results
3.1. Differences in brain volume
There were no significant group differences in the
total brain volume and in the intracranial volume. There
was also no difference in the absolute volume of the
target areas or in the relative volume compared with total
Table 2
Volumes (cm3) of specific regions of interest, absolute values, and group differences
Intracranial
Total brain
External CSF space
Third ventricle
Hippocampus, right
Hippocampus, left
Anterior cingulate, right
Anterior cingulate, left
Straight gyrus, right
Straight gyrus, left
Orbitofrontal cortex, right
Orbitofrontal cortex, left
Middle frontal gyrus, right
Middle frontal gyrus, left
Volumetric values represent mean F S.D.
a
Mann–Whitney U-test.
Control
Schizophrenia
(N = 13)
(N = 13)
1343.05 F 107.14
1228.20 F 102.19
114.86 F 26.63
0.94 F 0.31
2.84 F 1.14
2.84 F 1.11
3.33 F 0.93
3.41 F 0.84
2.74 F 0.62
2.85 F 0.66
9.92 F 1.83
10.96 F 1.58
14.27 F 2.28
14.16 F 2.77
1361.83 F 91.95
1231.77 F 93.12
130.06 F 30.02
1.16 F 0.47
3.00 F 0.78
3.11 F1.00
4.13 F 1.13
3.79 F 1.05
2.82 F 0.80
2.69 F 0.79
10.08 F 1.55
11.05 F 2.51
14.20 F 2.88
14.68 F 1.98
Pa
0.595
1.000
0.274
0.252
0.432
0.274
0.067
0.403
0.980
0.595
0.738
0.784
0.936
0.503
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Table 3
Volumes of specific regions of interest, relative values (%), and the
group differences
Hippocampus, right
Hippocampus, left
Anterior cingulate, right
Anterior cingulate, left
Straight gyrus, right
Straight gyrus, left
Orbitofrontal cortex, right
Orbitofrontal cortex, left
Middle frontal gyrus, right
Middle frontal gyrus, left
Control
Schizophrenia
(N = 13)
(N = 13)
0.23 F 0.09
0.23 F 0.09
0.27 F 0.08
0.31 F 0.09
0.22 F 0.04
0.23 F 0.04
0.81 F 0.14
0.89 F 0.11
1.17 F 0.19
1.17 F 0.19
0.25 F 0.07
0.26 F 0.09
0.34 F 0.10
0.28 F 0.07
0.23 F 0.06
0.22 F 0.06
0.83 F 0.10
0.90 F 0.16
1.16 F 0.25
1.20 F 0.20
Pa
0.347
0.322
0.085
0.347
0.742
0.231
0.738
0.563
0.979
0.611
Relative volumetric values represent mean F S.D.
a
Mann–Whitney U-test.
brain volume: the patient and the control groups did not
differ significantly in the volume of external CSF space,
third ventricle, bilateral hippocampi, SG, and the grey
matter of the orbitofrontal cortex, the middle frontal gyri
and the anterior cingulate gyri. There was only a tendency toward (absolute volume: P = 0.067, relative volume:
P = 0.085) a difference in the volume of anterior cingulum (increased in patients) on the right side, but no
differences were observed on the left side.
We investigated the lateral volume differences with a
two-way repeated measurements ANOVA with one
between-subjects factor (group: controls vs. patients)
and one within-subjects factor (side: left vs. right).
We found a significant interaction in the case of the
SG ( F(1, 24) = 4.731, P = 0.04) both for the absolute
and the relative volume; however, there was no significant group or side main effects. That means that lateralization of the SG was different in the two groups. In
healthy subjects the left SG was significantly larger
than the right SG, but in patients with schizophrenia
the case was just the reverse. In summary, we found
that the asymmetry of the SG was reversed in the
patient group with schizophrenia (Tables 2 and 3).
A similar tendency toward a hemispheric asymmetry
reversal was found in the volume of the anterior cingulate gyri (Group Side interaction: F(1, 24) = 1,282,
P = 0.269; group effect: F(1, 4) = 3.057, P = 0.093)
(Tables 2 and 3).
There was a significant main effect of lateralization
with left side dominance in the volume of the orbitofrontal cortex for both the absolute (F(1, 21) = 5.033,
P = 0.036) and relative values (F(1, 21) = 5.137, P =
0.034). However, there was not a significant Group
Side interaction.
3.2. Differences in neurocognitive parameters
We conducted Mann–Whitney U-tests to analyse the
performance on each cognitive task. We found significant group differences in verbal working memory performance measured by the Digit Span Forward and
Backward and the Nonword Repetition Tests and in
controlled association performance measured by Letter
(F,A,S) and Category (animals, fruits and vegetables,
Table 4
Neurocognitive parameters
WCST Completed categories
WCST Perseverative errors, %
WCST Conceptual Level Resp., %
WCST Failure to Maintain Set
Digit Span, forward
Digit Span, backward
Nonword Repetition Test
Corsi Blocks, forward
Corsi Blocks, backward
Visual Patterns Test
Tower of Hanoi (steps)
Letter fluency, words
Letter fluency, errors
Category fluency, words
Category fluency, errors
Values represent mean F S.D.
a
Mann–Whitney U-test.
* P (uncorrected): b 0.05.
** P (uncorrected): b 0.005.
Control
Schizophrenia
(N = 13)
(N = 13)
4.91 F 2.07
15.18 F 9.17
60.64 F 24.37
0.27 F 0.47
6.90 F 0.99
5.80 F 1.14
7.90 F 1.29
6.10 F 0.88
6.30 F 1.25
9.30 F 2.63
7.90 F 2.23
12.89 F 2.24
2.04 F 1.02
23.79 F 3.12
0.89 F 0.58
4.00 F 2.35
16.23 F 8.32
52.31 F 27.21
0.54 F 0.97
5.77 F 1.17*
4.23 F 1.01**
6.23 F 1.09**
6.46 F 0.88
5.85 F 1.35
7.54 F 1.81
11.00 F 5.31
8.56 F 2.41**
1.15 F 0.99
14.49 F 3.26**
0.91 F 0.82
Pa
0.228
0.608
0.531
0.776
0.030
0.004
0.004
0.410
0.446
0.088
0.208
0.001
0.067
0.000
0.656
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supermarket items) Fluency Tests, with a better performance for the control group in each case (Table 4).
There was no significant group difference in the
two visuo-spatial working memory tasks, the Corsi
tapping task and the Visual Pattern Task, and similarly, there were no differences in the Tower of Hanoi
task and in WCST performance (Table 4).
We found a significant difference between groups in
the frequency of neurological signs. The presence of abnormalities in sensory integration ( P b 0.001), motor coordination ( P b 0.05), and motor sequencing ( P b 0.001)
was significantly more frequent in the patient group
(Table 1). The appearance of neurological signs in the
patient group was independent from the extrapyramidal
side effects of the pharmacologic treatment.
3.3. Correlation between symptom severity and working memory performance
All patients were in an interepisodic, stable state
during investigation; there were only a few cases
where positive symptoms were present. As a consequence, positive symptoms had almost no impact on the
cognitive performance, with one exception: even a
small number of positive symptoms correlated negatively with the performance in the Category Fluency
task (r = 0.56, P b 0.05).
There were strong correlations between negative
symptoms and spatial working memory performance.
The affective scores of the SANS correlated negatively
with performance in the Visual Pattern Test (r = 0.575,
P b 0.05). The Corsi Blocks backward task also negatively
correlated with the attention (r = 0.564, P b 0.05) and
anhedonia (r = 0.560, P b 0.05) scores of the SANS.
The strongest correlations were found between planning function and severity of negative symptoms. The
performance on the Tower of Hanoi task negatively
correlated with almost all the subscales of the SANS:
Alogia (r = 0.7, P b 0.01), Avolition (r = 0.84,
P b 0.01), Anhedonia (r = 0.62, P b 0.05) and Attention (r = 0.83, P b 0.01). The performance on this
cognitive task also negatively correlated with the Negative subscale of the PANSS (r = 0.78, P b 0.01), and
also with the general (r = 0.63, P b 0.05) and the total
scores (r = 0.72, P b 0.01) of the PANSS.
3.4. Correlation between symptom severity and brain
volumes
As we mentioned before, all patients were in an
interepisodic, stable state during the investigation, and
as only few cases presented positive symptoms, we did
7
not expect strong correlations between brain volume
scores and positive symptoms.
The severity of negative symptoms measured by the
negative subscale of the PANSS correlated strongly with
the increased volume of the right hippocampus for both
the absolute (r = 0.69, P b 0.05) and the relative volume
measures (r = 0.58, P b 0.05). Within the negative symptom domain, the absolute volume of the right hippocampus also correlated with the severity of affective
flattening (r = 0.67, P b 0.05) measured by the SANS.
The relative volume of the left SG negatively correlated with the anhedonia scores (r = 0.60, P b 0.05) of
the SANS.
3.5. Correlation between course features and brain
volumes
The age at illness onset negatively correlated with
the absolute volume of the right middle frontal gyrus
(r = 0.6, P b 0.05), and positively correlated with the
volume of the external CSF space (r = 0.8, P b 0.01),
which also correlated with the chronological age of the
patients (r = 0.77, P b 0.01). The number of relapses
significantly correlated with the relative volume of the
right AC gyrus (r = 0.58, P b 0.05).
3.6. Correlation between brain volumes and cognitive
performance, independently of groups
The pattern we found with cross-correlation of brain
volumes and cognitive functions gave no clear picture,
so further investigations with larger subject pools are
required. There are some results, however, that are
worth mentioning: the increase of the volume of the
third ventricle negatively correlated with WAIS IQ
score (r = 0.44, P b 0.05), with two subscores of the
WCST (Completed Categories: r = 0.521, P b 0.05;
Conceptual Level Responses: r = 0.47, P b 0.05).
The visuo-spatial working memory performance measured by the VPT negatively correlated with absolute
(r = 0.43, P b 0.05) and relative volume of the SG
(r = 0.45, P b 0.05). The volume of the left middle
frontal gyrus positively correlated with performance the
backward digit span task (r = 0.46, P b 0.05), which is a
combined measurement of verbal working memory and
executive function.
3.7. Correlation between NES scores and extrapyramidal symptoms
There was no significant correlation between scores
of neurological signs (NES) and the extrapyramidal
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I. Szendi et al. / Psychiatry Research: Neuroimaging xx (2006) xxx–xxx
side effects of pharmacologic treatments (SAS, BAS,
AIMS scores).
4. Discussion
Schizophrenia is a multifocal brain disease yielding
various correlations between structural and functional
brain changes and clinical and cognitive symptoms.
There are unitary and heterogeneous theories of schizoprenia. Our research group considers schizophrenia
to be a heterogeneous disease, so we use methods and
interpret results within a cognitive neuropsychiatric
theoretical framework, with the aim of identifying coherent etiological subgroups within schizophrenia. At
present our results do not allow us to define relevant
subgroups, but they should be considered as a first step
in this process.
Our main finding is a change in asymmetry of the
SG, a brain area where, according to our current knowledge, no such difference has been detected in schizophrenia. One recent study found decreased volume of
the SG in major depression (Bremner et al., 2002), and
another one found a strong correlation between decreased volume and surface of the SG and social dysfunction (Chemerinski et al., 2002). These findings
underlie the importance of these regions in the appearance of schizophrenic symptoms. The SG (BA 11) is
situated medially to the olfactory groove (olfactory
sulcus) at the ventromedial edge of the frontal lobe,
and is considered to be the frontal extension of the
anterior cingulate gyrus. The SG has dense inhibitory
connections with the superior temporal gyrus (STG)
and the centres of the auditory cortex, and it is part of
the emotional–memory network involved in the recall
of episodic and autobiographical memories and also in
the short-term maintenance of visuo-spatial information
(Szatkowska et al., 2001). The change in laterality of
the SG may refer to the dysfunctional operation of this
region which might play a significant role in the symptoms of self-disorder and hallucinations in schizophrenia. On the basis of this result, further structural and
functional analyses of this brain region in schizophrenia
seem to be promising.
In the present phase of our research we did not find a
significant difference in the volume of intracranial
space, total brain volume, and relative volume of specific target regions between male patients with schizophrenia and healthy control subjects. We found
significant group differences in verbal working memory
and executive function performance, such as the backward digit span and fluency tasks. However, there were
no group differences in tasks involving planning and
strategy shifting such as the WCST and the Tower of
Hanoi. There was a significant group difference in the
frequency of neurological signs; patients with schizophrenia had significantly higher scores on the NES
subscales of sensory integration, motor coordination,
motor sequencing, and the total score of neurological
signs. Negative symptoms showed correlations with
spatial working memory and planning functions.
Among the assessed cognitive functions, planning
was the most sensitive to the presence of negative
symptoms. Negative symptoms were restated to the
increase of the right hippocampus volume, and the
relative volume of left SG correlated negatively with
the scores of the anhedonia subscale.
The results of our preliminary report should be
interpreted with caution. Here we presented the uncorrected P-values, so the strongest correlations are the
most acceptable ones. Although some of them are
consistent and others are inconsistent with earlier findings, they should be examined in further studies with
larger patient samples involving female subjects, and
also with larger numbers of control persons matched for
education and IQ scores.
Acknowledgement
This study was supported by grants NKFP 50079/
2002 (Hungarian National Research Grant for the project dCognitive and Neural PlasticityT), OTKA T
046152/2004 (Hungarian Scientific Research Fund),
OTKA T 034814 (Hungarian Scientific Research
Fund), and ETT IV/93/2003 (Hungarian Ministry of
Health).
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