Asian Journal of Psychiatry 25 (2017) 197202

Contents lists available at ScienceDirect

Asian Journal of Psychiatry

journal homepage: www.elsevier.com/locate/ajp

Callosal size in rst-episode schizophrenia patients with illness

duration of less than one year: A cross-sectional MRI study
Michio Takahashia , Mie Matsuia,b,* , Mitsuhiro Nakashimaa , Tsutomu Takahashic ,
Michio Suzukic
a
b
c

Department of Psychology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama, Japan
Institute of Liberal Arts and Science, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, Japan
Department of Neuropsychiatry, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama, Japan

A R T I C L E I N F O

Article history:
Received 16 June 2016
Received in revised form 17 October 2016
Accepted 29 October 2016
Available online xxx
Keywords:
Corpus callosum
MRI
First episode
Schizophrenia
Negative symptom

A B S T R A C T

Previous studies have reported a reduction in the size of the corpus callosum (CC) on the mid-sagittal
plane in patients with schizophrenia. However, ndings for the size of the callosal area in patients with
rst-episode schizophrenia (FESz) are inconsistent. A possibility for these conicting results is that the
duration of illness in patients with FESz affects the CC size. The present study investigated the CC size
abnormalities in patients with FESz. Forty-six patients with FESz whose duration of illness was less than
1 year and 46 age-, sex-, and handedness-matched healthy controls were recruited to examine the CC size
using magnetic resonance imaging. We measured the area of the CC using the Witelsons scheme, which
divided the whole area into seven subdivisions. Analysis of covariance indicated there was no difference
in the whole or regional areas of the CC between patients with FESz and healthy controls. The rostrum of
the CC was signicantly correlated with the total score for negative symptoms and some of the subtotal
scores. Our ndings indicate that there was no reduction in the whole or regional area of the CC among
patients with FESz. When comparing the callosal morphology and symptoms, negative symptoms
increased in severity as the rostrum area of the CC decreased in size. Further studies are needed to
investigate whether the size of the anterior CC is associated with the pathology observed in the early
stages of FESz.
2016 Elsevier B.V. All rights reserved.

1. Introduction
The corpus callosum (CC) is a major commissural ber
connecting each hemisphere of the brain. It was presumed that
the pathology observed in patients with schizophrenia involved
dysfunctions in neural connectivity; thus, the CC has been the
primary focus for schizophrenia research (David, 1994). Previous
studies using magnetic resonance imaging (MRI) have shown
morphological abnormalities associated with schizophrenia
(Woodruff et al., 1995; Arnone et al., 2008). Results from studies
indicated that a delay or reduction in myelination occurs in the CC
of individuals with schizophrenia (Innocenti et al., 2003; Crow
et al., 2007).

* Corresponding author at: Institute of Liberal Arts and Science, Kanazawa

University, Kakuma machi, Kanazawa, Ishikawa 930-0194, Japan.
E-mail addresses: takahashi.psy@gmail.com (M. Takahashi),
miematsui@staff.kanazawa-u.ac.jp (M. Matsui), mnakashima1203@outlook.jp
(M. Nakashima), tsutomu@med.u-toyama.ac.jp (T. Takahashi),
suzukim@med.u-toyama.ac.jp (M. Suzuki).
http://dx.doi.org/10.1016/j.ajp.2016.10.031
1876-2018/ 2016 Elsevier B.V. All rights reserved.

In studies on rst-episode schizophrenia (FESz), patients with

FESz also exhibited smaller whole and regional areas of the CC than
healthy individuals (Hendren et al., 1995; Keshavan et al., 2002;
Bachmann et al., 2003; Collinson et al., 2014). However, two studies
reported inconsistent results and did not nd reductions in the
whole and regional areas of the CC in patients with FESz (Hoff et al.,
1994; Walterfang et al., 2008a). One of the reasons for these
inconsistent ndings may be due to the confounding effect of
illness duration. The studies that reported a reduction of the CC
area included patients whose average illness duration was
comparatively long (ranging from approximately 2 to 4 years)
(Keshavan et al., 2002; Collinson et al., 2014). In contrast, the other
studies that demonstrated no reduction included patients whose
average illness duration was less than 1 year (Hoff et al., 1994;
Walterfang et al., 2008a). Another morphological study showed
similar results with regard to the relationship between illness
duration and brain morphology. Molina et al. (2004) found that the
prefrontal gray matter volume in patients with FESz whose illness
duration was less than 1 year was not signicantly reduced
compared to healthy controls, while in short-term chronic patients

198

M. Takahashi et al. / Asian Journal of PsychiatryAJP 25 (2017) 197202

with illness duration ranged from 1.5 to 6 years, the volume

signicantly decreased. Accordingly, signicant morphological
changes in the CC of patients with FESz having illness duration
of less than 1 year may not have occurred. However, there have
been no studies to investigate the morphological changes in the CC,
including only the patients with FESz whose illness duration was
less than 1 year.
Another challenge for studying the CC is to establish the
subregions of the CC whose volumes are possibly reduced in
patients with FESz. Various methods for dividing the CC into
subregions have been proposed. Among them, the most popular
method was proposed by Witelson (1989), which dened
subdivisions of CC based on anatomical connectivity. In a study
on FESz, Keshavan et al. (2002) used a method based on the
Witelsons scheme to examine morphological abnormalities and
reported regional reduction in the CC. However, this method has
not been used to investigate abnormalities of the CC in patients
with FESz having illness duration of less than 1 year.
The aims of this study were to examine the whole and regional
areas of the CC using the Witelsons scheme and to investigate the
morphological abnormalities of the CC within patients with FESz
whose duration of illness is comparatively short (less than 1 year).
These changes were compared to age-, sex-, and handednessmatched controls to avoid the inuence of confounding factors
known to affect callosal size (Witelson, 1989). Furthermore, we
explored the relationships between the CC area and illness
characteristics and symptoms.
2. Methods
2.1. Participants
The present study included 46 patients with FESz who met the
ICD-10 research criteria for schizophrenia (World Health Organization, 1993). All patients were recruited from inpatient and
outpatient clinics of the Department of Neuropsychiatry of Toyama
University Hospital. All patients were followed up regularly also
after MRI scanning by experienced psychiatrists, and the diagnosis
of schizophrenia was conrmed for all cases at least 6 months after
the onset of illness based on the information acquired from a
detailed chart review. Patients with FESz were dened as those
experiencing their rst episode of schizophrenia and whose illness
onset was within 1 year at the time of scanning. Clinical symptoms
were assessed using the Scale for the Assessment of Negative
Symptoms (SANS) and the Scale for the Assessment of Positive
Symptoms (SAPS) (Andreasen, 1984).
A total of 46 age- and sex-matched healthy individuals were
also recruited from among the community, hospital staff, and

university students. They were administered a questionnaire

consisting of 13 items concerning their personal history of illness
(e.g., history of obstetric complications, substantial head injury,
seizures, neurological or psychiatric diseases, and substance use)
and two items concerning their family history of illness. They did
not have any personal or family history of psychiatric illness among
their rst-degree relatives.
All participants were right-handed on the basis of a handedness
rating scale (Okada et al., 2014) and were physically healthy. None
of the participants had a serious head trauma, neurological illness,
substance abuse disorder, or serious medical disease, but we did
not assess their cigarette smoking behavior. All participants were
screened for gross brain abnormalities by neuroradiologists.
Demographic and clinical information of the participants are
shown in Table 1. There was no signicant difference in the
demographic data except for the education level between patients
with FESz and controls. There was no difference in all demographic
data between males and females. For clinical information of illness,
the age at onset for females was earlier than that for males
(t = 2.053, p = 0.046), whereas other clinical information was not
signicantly different (all p > 0.05). A possible explanation for
females exhibiting an earlier age at onset in contrast to previous
studies (e.g., Castle et al., 1998; Hfner et al., 1998) was that our
study included only adolescent and young adults because the age
range of patients with schizophrenia inuences results regarding
the sex difference in age at onset (Thorup et al., 2007; Venkatesh
et al., 2008). In this study, the age range of patients with FESz was
relatively narrow (males: 16.937.6 years, females: 16.727.7
years).
This study was approved by the Committee on Medical Ethics of
Toyama University. Written informed consent was obtained from
all participants after the procedures had been fully explained.
2.2. Image acquisition
T1-weighted images were scanned using a 1.5-T Magnetom
Vision (Siemens Medical System, Inc., Erlangen, Germany) with
three-dimensional gradient-echo sequence FLASH (fast low-angle
shots) yielding contiguous slices of 1.0 mm thickness in the sagittal
plane. The imaging parameters were as follows: repetition
time = 24 ms, echo time = 5 ms, ip angle = 40 , eld of view = 256
mm, and matrix size = 256  256 pixels. The voxel size was
1.0  1.0  1.0 mm.
2.3. Image analysis
Each T1-weighted image was realigned to standardize for
difference in head till during the scanning and were then

Table 1
Demographic and clinical data of participants.
Patients with FESz

Age (years)
Education (years)
Parental education (years)
Age at onset (years)
Duration of illness (months)
Duration of medication (months)
HPD equivalent (mg/day)
SAPS total score
SANS total score
Intracranial volume (cm3)
Total brain volume (cm3)

Control

Diagnosis group comparison

male (n = 26)

female (n = 20)

male (n = 26)

female (n = 20)

25.1  5.2
13.4  2.1
13.1  2.3
24.7  5.1
4.3  2.6
2.8  2.7
10.6  9.4
24.8  24.5
47.3  25.2
1522.4  118.9
1233.9  130.1

22.6  3.2
13.5  2.1
13.1  1.9
22.2  3.3
6.0  3.8
4.1  8.1
7.1  8.3
29.9  20.5
57.5  23.2
1 344.9  86.3
1117.2  71.7

25.9  3.3
17.8  2.0
13.7  2.1

1542.2  108.6
1252.7  89.6

25.1  5.5
15.3  1.6
13.6  2.5

1301.0  78.0
1087.1  70.7

t = 1.630
t = 7.422
t = 0.281

t = 0.247
t = 0.101

p = 0.107
p < 0.001
p = 0.779

p = 0.805
p = 0.920

Data are shown as mean  S.D. FESz, First-episode schizophrenia; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative
Symptoms.

M. Takahashi et al. / Asian Journal of PsychiatryAJP 25 (2017) 197202

reconstructed into entire contiguous coronal images of 1-mm

thickness vertical to the anterior commissure-posterior commissure line. We delineated the whole CC area and divided the area
into seven subdivisions using ANALYZE 11.0 (Mayo Foundation,
Rochester, Minn., USA) on the mid-sagittal section using the
Witelsons scheme (1989) (Fig. 1 and Supplement Fig. S1). To
identify the mid-sagittal slice, we referred to the denition
provided by Giedd et al. (1999).
We calculated the total gray matter, white matter, and
cerebrospinal uid volumes using SPM12. Then, the total brain
volume (TBV) was calculated by summing the total gray matter and
white matter volumes. The intracranial volume (ICV) was
calculated by summing the total gray matter and white matter
with the cerebrospinal uid volumes. Both ICV and TBV were not
signicantly different between the diagnostic groups (Table 1),
whereas there were signicant sex differences in the ICV
(F(1,90) = 95.545, p < 0.001) and TBV (F(1,90) = 48.817, p < 0.001).
2.4. Measurement of reliability
Ten data images, including those of ve controls and ve
patients, were randomly selected to examine the inter- and intrarater reliabilities of measurement. Inter-rater reliability was
estimated for two independent raters (M.T. and M.N.) who were
blinded to whether the image data belonged to the control or
patient groups. Intraclass correlation (ICC) analysis for the whole
CC area yielded a value of 0.97, and the seven subdivisions yielded
values ranging from 0.85 to 0.99. Intra-rater reliabilities of
measurement were examined for one rater (M.T.) at two separate
time points with intervals of approximately 2 months. The ICC
coefcient for the whole CC area was 0.97 and ranged from 0.88 to
0.99 for the seven subdivisions.
2.5. Statistical analysis
We used SPSS ver.22 to analyze the data. The diagnosis or sex
differences of the demographic and clinical data were examined by
Students t-test. The whole and seven subdivisions of the CC were
also compared by analysis of covariance (ANCOVA) using diagnosis
and sex as between-group factors, part of the subdivisions as the
within-subject factor, and ICV and age as covariates. Age and ICV
were used as covariates because these factors could signicantly
affect brain morphology (Kruggel, 2006; Sowell et al., 2003). The
post hoc Bonferroni tests were employed to follow up the
signicance main effects or interactions. Correlation analysis
was performed using Pearsons correlation coefcient to examine
the relationships between the CC area and (1) demographic
variables among all participants; (2) illness characteristics
including age at onset, duration of illness and medication, and
the amount of medication, and (3) symptoms of schizophrenia

199

among patients with FESz. We dened statistical signicance as

p < 0.05.
3. Results
3.1. Comparison of the CC area
The mean size of the whole CC area and its subdivisions are
listed in Table 2. Analysis of covariance of the CC areas did not show
main effects for diagnosis (F(1,86) = 0.305, p = 0.582) or region
(F(6,516) = 1.235,
p = 0.287).
Similarly,
diagnosis  region
(F(6,516) = 0.747,
p = 0.612),
diagnosis  sex
(F(1,86) = 0.079,
p = 0.780) or diagnosis  sex  region (F(6,516) = 1.663, p = 0.128)
interactions were not signicant. These results implied that there
was no difference in the whole or regional areas of the CC between
patients with FESz and healthy controls. Whereas, there was a
signicant main effect for sex (F(1,86) = 7.906, p = 0.006). Post hoc
analysis for sex effect on subregions showed that females had a
signicantly larger splenium (p = 0.006). Additionally, the result of
Post hoc test showed that females had a larger genu (p = 0.053) and
posterior midbody (p = 0.085), although these were at a trend level.
In addition, these ANCOVA results remained the same even when
we used TBV as covariate instead of ICV.
3.2. Correlation analysis
There were signicant, but weak, positive correlations between
the age and the whole CC (r = 0.220, p = 0.035) and splenium
(r = 0.231, p = 0.007) areas, as well as year of parental education and
the anterior midbody area (r = 0.244, p = 0.019) among all
participants. Clinically, the age at onset was signicantly correlated
with the rostrum (r = 0.322, p = 0.029) and splenium (r = 0.299,
p = 0.044) areas, but these correlations were not signicant after
controlling for ICV or TBV (all partial r, p > 0.05). The duration of
illness, dose, and duration of medication were not signicantly
correlated to any subdivision areas (all p > 0.05). Regarding the
symptoms of schizophrenia, the rostrum area negatively correlated
to the SANS total score (Fig. 2), both before and after controlling for
ICV (r = 0.344, p = 0.016) or TBV (r = 0.380, p = 0.010). There were
also signicant negative correlations between the rostrum area
and some subtotal SANS scores, including affective attening
(r = 0.371, p = 0.011), avolition (r = 0.312, p = 0.035), and anhedonia (r = 0.377, p = 0.010). These relationships regarding the
rostrum area and subtotal scores also remained signicant after
controlling for ICV or TBV (all partial r, p < 0.05). However, none of
the relationships between area size and negative symptoms were
signicant after Bonferroni correction with statistical signicance
set as p < 0.0035. In contrast, the whole and subdivision areas of CC
were not signicantly associated with the total and subtotal scores
on the SAPS (all p > 0.05). There was no correlation found between
symptoms of schizophrenia and ICV and TBV (all p > 0.05).
4. Discussion

Fig. 1. Percellation of the corpus callosum area by Witelsons method (1989) 1rostrum, 2-genu, 3-rostral body, 4-anterior midbody, 5-posterior midbody, 6isthmus, and 7-splenium.

In the present study, we examined the morphology of the CC in

patients with FESz compared to age-, sex-, and handednessmatched controls as well as the association of the CC area with FESz
clinical characteristics. The main nding of our study was that
there was no reduction in either the whole or regional areas of the
CC in patients with FESz compared to healthy individuals. Our
ndings for the whole CC are consistent with some previous
studies of FESz, which included subjects whose illness duration
was less than 1 year (Hoff et al., 1994; Walterfang et al., 2008a), but
different from other studies that included subjects with illness
duration of over 2 years (Keshavan et al., 2002; Collinson et al.,
2014). Although there are two other studies that reported a

200

M. Takahashi et al. / Asian Journal of PsychiatryAJP 25 (2017) 197202

Table 2
The raw and adjusted size of corpus callosum.
Adjusted value (mean)a

Unadjusted value (mean  S.D.)

Patients with FESz

Rostrum
Genu
Rostral body
Anterior midbody
Posterior midbody
Isthmus
Splenium
Total area

male
(n = 26)
21.2  8.6
136.6  25.2
87.7  14.6
77.2  10.6
70.6  11.6
54.2  12.8
175.4  28.3
622.8  86.6

Control
female
(n = 20)
18.5  6.4
138.6  23.4
85.4  16.4
75.9  8.4
68.4  10.1
48.0  10.2
169.2  19.9
603.9  53.7

male
(n = 26)
18.4  7.9
141.3  21.3
89.9  13.9
79.3  9.8
68.2  10.9
48.9  11.0
183.0  25.4
628.8  75.4

female
(n = 20)
18.4  9.3
125.6  21.6
81.6  16.0
72.2  9.5
68.1  10.0
47.8  10.4
167.7  24.8
580.8  74.1

Patients with FESz

Control

male
(n = 26)
19.4
129.3
82.7
74.4
68.2
51.2
164.7
589.8

male
(n = 26)
15.9
131.8
83.9
75.8
64.9
45.1
168.9
586.2

female
(n = 20)
21.1
148.5
90.7
79.3
72.0
51.7
183.8
647.1

female
(n = 20)
21.3
137.8
90.1
76.8
72.0
52.7
185.3
635.9

FESz, First-episode schizophrenia; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative Symptoms.
a
Adjusted for ICV and age.

50

r = -0.379
p = 0.009

Rostrum area (mm2)

40

30

20

10

0
0

20

40

60

80

100

SANS total score

Fig. 2. Scatter plot depicting the correlation between the rostrum of the corpus
callosum and negative symptoms measured by Scale for the Assessment Negative
Symptoms (SANS) among patients with rst-episode schizophrenia.

reduction in the whole area (Hendren et al., 1995; Bachmann et al.,

2003), it was impossible to compare from the view of illness
duration as these studies did not clearly describe illness duration.
As mentioned in the Introduction section, these conicting results
for the reduction in CC size might be due to the duration of illness.
In line with this notion, there was no reduction in the whole CC
area in recent-onset drug-naive schizophrenia patients whose
average illness duration was approximately 70 weeks (John et al.,
2008), while reduction in the whole CC area was observed in drugnaive patients whose average illness duration was longer than 3
years (Venkatasubramanian et al., 2010). Furthermore, longitudinal studies have shown that the whole CC area in patients with
FESz and those with chronic schizophrenia signicantly decreased
over 4 years, while that of a healthy individual remained steady or
even increased (DeLisi et al., 1995; Mitelman et al., 2009).
In addition, the present study did not nd a reduction in the
regional areas of the CC in patients with FESz, as well as in the
whole area, which is in accordance with a previous study (Hoff
et al., 1994). Some studies on FESz have reported a regional
reduction in the CC area in various partitions, but patients with
FESz who were included in these studies had longer durations of
illness (Keshavan et al., 2002; Collinson et al., 2014). These results
suggest that the regional reduction observed in patients with
schizophrenia is inuenced by illness duration. Cross-sectional
studies have shown that the regional size of the CC is negatively
correlated with the duration of illness (Downhill et al., 2000;
Collinson et al., 2014) and that the subregion of the CC that featured

a reduced area or width differed between patients with FESz and

those with chronic schizophrenia (Walterfang et al., 2008a;
Collinson et al., 2014). It should be noted that individuals with
ultra-high risk for psychosis who developed a schizophreniaspectrum illness exhibited very subtle, but signicant, morphological changes in the anterior CC but no reduction in the whole CC
(Walterfang et al., 2008b). Similarly, it was shown that the regional
callosal width was reduced in patients with FESz (Walterfang et al.,
2008a). Therefore, subtle morphological changes that did not
reect area size may exist in the CC of patients with FESz. However,
this study failed to demonstrate an immediate relationship
between the duration of illness and the whole and subdivision
areas of the CC. This may be attributed to the age range of the
participants, which was narrow as this study included patients
whose average illness duration was 5.1  3.2 months.
This study demonstrated that the whole area and some regional
areas of the CC in females were signicantly larger than those of
males, irrespective of the diagnosis group. The sexual dimorphism
of relative CC size has been reported in many MRI studies on
healthy individuals (Witelson, 1989; Ardekani et al., 2013) and one
study in patients with FESz (Bachmann et al., 2003). However,
other studies have shown conicting sex differences in patients
with FESz (Hoff et al., 1994; Keshavan et al., 2002; Walterfang et al.,
2008a; Collinson et al., 2014). Regarding subdivisions of the CC, we
demonstrated sex differences in the area of the genu, posterior
midbody, and splenium. This analysis showed that the area of the
CC subdivisions in females was signicantly larger than that in
males. These ndings are in accordance with previous developmental studies of the CC using the same partition method (TanakaArakawa et al., 2015), which reported that women had a larger
mean ratio of the genu, posterior midbody, and splenium of the CC
than men throughout their life.
Correlation analyses demonstrated that the rostrum area of the
CC negatively correlated with the total and some subtotal scores of
the SANS, although these relationships were not signicant after
Bonferroni correction. These results suggest that the negative
symptoms were more severe as the rostrum area was smaller.
Previous studies have demonstrated a similar relationship
between the whole CC area and the negative symptom score with
the SANS of patients with schizophrenia (Woodruff et al., 1997;
Tibbo et al., 1998), although there was no signicant difference in
the CC area between patients and controls (Woodruff et al., 1997;
Tibbo et al., 1998). Additionally, Woodruff et al. (1997) showed that
the anterior part of the CC correlated with the total and some
subtotal scores, including affective attening, avolition, and
anhedonia on the SANS, which are the subitems that completely
corresponded to our ndings. The rostrum of the CC is assumed to
connect to the orbital prefrontal cortex (Abe et al., 2004; Huang
et al., 2005), and Gur et al. (2000) demonstrated that a reduction in

M. Takahashi et al. / Asian Journal of PsychiatryAJP 25 (2017) 197202

the orbital prefrontal cortex was associated with more sever

negative symptoms. In some diffusion tensor imaging studies, it
has been shown that the fractional anisotropy value of the anterior
part of the CC correlated with negative symptoms in patients with
FESz (Kubicki et al., 2008; Nakamura et al., 2012). However, other
studies using Witelsons scheme for partitioning the CC found no
relationship between CC areas and negative symptoms (Goghari
et al., 2005; Bersani et al., 2010; Venkatasubramanian et al., 2010).
The relationship between a reduced CC area and symptoms of
schizophrenia may be caused by global atrophy of the brain. For
example, dAmato et al. (1992) showed that the severity of negative
symptoms was associated with a reduced brain volume and
ventricular enlargement. In recent studies, similar tendencies have
been shown for the total and regional gray matter volumes among
patients with rst-episode psychosis (Berg et al., 2011; Reig et al.,
2011). In this study, however, there was no signicant difference in
the ICV and TBV between patients and controls, and there was no
correlation between negative symptoms and ICV and TBV among
patients with FESz. These results suggest that the rostrum area is
associated with the negative symptoms of patients with FESz,
which is independent from the global atrophy of the brain.
However, it should be considered that our results did not
demonstrate a change in the size of the rostrum; therefore, these
results should be regarded as preliminary. Furthermore, patients
with FESz in the present study exhibited predominantly negative
symptoms, although their illness duration was comparatively
short, which could inuence the results for the relationships
between negative symptoms and CC morphology. A possible
reason for the predominantly negative symptoms is that the
patients in the present study were scanned following the
treatment for the acute phase of schizophrenia. To address this
point, further studies on drug-naive FESz patients whose illness
duration is less than 1 year are required.
This study has several limitations. First, patients with FESz in
our study were not drug-naive, and antipsychotic medications may
contribute to structural changes in the white matter (Girgis et al.,
2006; Bartzokis et al., 2007; Navari and Dazzan, 2009). Further
study will be need to examine the CC size with drug-naive FESz
patients whose duration of illness is short. Second, the healthy
comparison subjects in this study were screened using a selfreported questionnaire but not a formal structured clinical
interview, representing a limitation of this study. Third, we
measured the CC area size, but not other morphological features
(e.g., width and volume). These morphological features may be
more sensitive to morphological changes in the CC than the area
size on the mid-sagittal plane (Walterfang et al., 2008a; Collinson
et al., 2014). Fourth, the present study might be partly limited by
the lack of a detailed clinical assessment, including the severity of
rst-rank symptoms. A previous study demonstrated the effect of
rst-rank symptoms on the subregional area of CC in drug-naive
schizophrenia patients (Rao et al., 2011). Finally, this study had a
cross-sectional design. Further longitudinally designed studies will
be needed to clarify the relationships between duration or
chronicity of illness and CC morphology.
In conclusion, our ndings indicate that there was no reduction
in the whole or regional areas in the mid-sagittal section among
patients with FESz. These results are in accordance with some
previous studies and not in agreement with others. This
discrepancy may be due to differences in the illness duration in
patients between these studies. It was indicated that the change in
the CC area did not exist or was not noticeable in patients with FESz
whose duration of illness was comparatively short, although subtle
morphological changes do exist. Furthermore, this study demonstrates that the rostrum area of the CC inversely correlated with
negative symptoms, suggesting that the anterior part of the CC is

201

associated with the pathology of early stage FESz, although this

result should be considered as preliminary.
Acknowledgement
This study was supported by JSPS KAKENHI Grant Number
JP26118707, JP26285155, JP26590143 and a Grant-in-Aid for
Scientic Research on Innovative Areas (Comprehensive Brain
Science Network) from the Ministry of Education, Science, Sports
and Culture of Japan.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.ajp.2016.10.031.
References
Abe, O., Masutani, Y., Aoki, S., Yamasue, H., Yamada, H., Kasai, K., Mori, H., Hayashi,
H., Masumoto, T., Ohtomo, K., 2004. Topography of the human corpus callosum
using diffusion tensor tractography. J. Comput. Assist. Tomogr. 28 (4), 533539.
Andreasen, N.C., 1984. Scale for the Assessment of Negative Symptoms/Scale for the
Assessment of Positive Symptoms [Manual]. University of Iowa Press, Iowa City.
Ardekani, B.A., Figarsky, K., Sidtis, J.J., 2013. Sexual dimorphism in the human corpus
callosum: an MRI study using the OASIS brain database. Cereb. Cortex 23 (10),
25142520.
Arnone, D., McIntosh, M.A., Tan, G.M.Y., Ebmeier, K.P., 2008. Meta-analysis of
magnetic resonance imaging studies of the corpus callosum in schizophrenia.
Schizophr. Res. 101 (13), 124132.
Bachmann, S., Pantel, J., Flender, A., Bottmer, C., Essig, M., Schorder, J., 2003. Corpus
callosum in rst-episode patients with pchizophreniaa magnetic resonance
imaging study. Psychol. Med. 33 (6), 10191027.
Bartzokis, G., Lu, P.H., Keith Nuechterlein, H., Gitlin, M., Doi, C., Edwards, N., Lieu, C.,
Altshuler, L.L., Mintz, J., 2007. Differential effects of typical and atypical
antipsychotics on brain myelination in schizophrenia. Schizophr. Res. 93, 1322.
Berg, D., Carmona, S., Rovira, M., Bulbena, A., Salgado, P., Vilarroya, O., 2011. Gray
matter volume decits and correlation with insight and negative symptoms in
rst-psychotic-episode subjects. Acta Psychiatr. Scand. 123 (6), 431439.
Bersani, G., Quartini, A., Iannitelli, A., Paolemili, M., Ratti, F., Di Biasi, C., Gualdi, G.,
2010. Corpus callosum abnormalities and potential age effect in men with
schizophrenia: an MRI comparative study. Psychiatry Res. 183 (2), 119125.
Castle, D., Sham, P., Murray, R., 1998. Differences in distribution of ages of onset in
males and females with schizophrenia. Schizophr. Res. 33 (3), 179183.
Collinson, S.L., Gan, S.C., Woon, P.S., Kuswanto, C., Sum, M.Y., Yang, G.L., Lui, J.M.,
Sitoh, Y.Y., Nowinski, W.L., Sim, K., 2014. Corpus callosum morphology in rstepisode and chronic schizophrenia: combined magnetic resonance and
diffusion tensor imaging study of Chinese Singaporean patients. Br. J. Psychiatry
204 (1), 5560.
Crow, T.J., Paez, P., Chance, S.A., 2007. Callosal misconnectivity and the sex difference
in psychosis. Int. Rev. Psychiatry 19 (4), 449457.
dAmato, T., Rochet, T., Dalery, J., Laurent, A., Chauchat, J.H., Terra, J.L., Marie-Cardine,
M., 1992. Relationship between symptoms rated with the positive and negative
syndrome scale and brain measures in schizophrenia. Psychiatry Res. 44 (1), 55
62.
David, A.S., 1994. Schizophrenia and the corpus callosum: developmental:
structural and functional relationships. Behav. Brain Res. 64, 203211.
DeLisi, L.E., Tew, W., Xie, S., Hoff, A.L., Sakuma, M., Kushner, M., Lee, G., Shedlack, K.,
Smith, A.M., Grimson, R., 1995. A prospective follow-up study of brain
morphology and cognition in rst-episode schizophrenic patients: preliminary
ndings. Biol. Psychiatry 38 (6), 349360.
Downhill Jr., J.E., Buchsbaum, M.S., Wei, T., Spiegel-Cohen, J., Hazlett, E.A., Haznedar,
M.M., Silverman, J., Siever, L.J., 2000. Shape and size of the corpus callosum in
schizophrenia and schizotypal personality disorder. Schizophr. Res. 42 (3), 193
208.
Giedd, J.N., Blumenthal, J., Jeffries, N.O., Rajapakse, J.C., Vaituzis, A.C., Liu, H., Berry, Y.
C., Tobin, M., Nelson, J., Castellanos, F.X., 1999. Development of the human
corpus callosum during childhood and adolescence: a longitudinal MRI study.
Prog. Neuropsychopharmacol. Biol. Psychiatry 23 (4), 571588.
Girgis, R.R., Diwadkar, V.A., Nutche, J.J., Sweeney, J.A., Keshavan, M.S., Hardan, A.Y.,
2006. Risperidone in rst-episode psychosis: a longitudinal, exploratory VoxelBased Morphometric study. Schizophr. Res. 82 (1), 8994.
Goghari, V.M., Donna, J.L., Sean, W.F., Alex, L.M., William, G.H., 2005. Smaller corpus
callosum subregions containing motor bers in schizophrenia. Schizophr. Res.
73 (1), 5968.
Gur, R.E., Cowell, P.E., Latshaw, A., Turetsky, B.I., Grossman, R.I., Arnold, S.E., Bilker,
W.B., Gur, R.C., 2000. Reduced dorsal and orbital prefrontal gray matter volumes
in schizophrenia. Arch. Gen. Psychiatry 57 (8), 761768.
Hfner, H., an der Heiden, W., Behrens, S., Gattaz, W.F., Hambrecht, M., Lfer, W.,
Maurer, K., Munk-Jrgensen, P., Nowotny, B., Riecher-Rssler, A., Stein, A., 1998.

202

M. Takahashi et al. / Asian Journal of PsychiatryAJP 25 (2017) 197202

Causes and consequences of the gender difference in age at onset of

schizophrenia. Schizophr. Bull. 24 (1), 99113.
Hendren, R.L., Hodde-Vargas, J., Yeo, R.A., Vargas, L.A., Brooks, W.M., Ford, C., 1995.
Neuropsychophysiological study of children at risk for schizophrenia: a
preliminary report. J. Am. Acad. Child. Adolesc. Psychiatry 34 (10), 12841291.
Hoff, A.L., Neal, C., Kushner, M., DeLisi, L.E., 1994. Gender differences in corpus
callosum size in rst-episode schizophrenics. Biol. Psychiatry 35 (12), 913919.
Huang, H., Zhang, J., Jiang, H., Wakana, S., Poetscher, L., Miller, M.I., van Zijl, P.C.,
Hillis, A.E., Wytik, R., Mori, S., 2005. DTI tractography based parcellation of
white matter: application to the mid-sagittal morphology of corpus callosum.
Neuroimage 26 (1), 195205.
Innocenti, G.M., Ansermet, F., Parnas, J., 2003. Schizophrenia, neurodevelopment
and corpus callosum. Mol. Psychiatry 8 (3), 261274.
John, J.P., Shakeel, M.K., Jain, S., 2008. Corpus callosal area differences and gender
dimorphism in neuroleptic-nave, recent-onset schizophrenia and healthy
control subjects. Schizophr. Res. 103 (13), 1121.
Keshavan, M.S., Diwadkar, V.A., Harenski, K., Rosenberg, D.R., Sweeney, J.A.,
Pettegrew, J.W., 2002. Abnormalities of the corpus callosum in rst episode,
treatment naive schizophrenia. J. Neurol. Neurosurg. Psychiatry 72 (6), 757760.
Kruggel, F., 2006. MRI-based volumetry of head compartments: normative values of
healthy adults. Neuroimage 30 (1), 111.
Kubicki, M., Styner, M., Bouix, S., Gerig, G., Markant, D., Smith, K., Kikinis, R.,
McCarley, R.W., Shenton, M.E., 2008. Reduced interhemispheric connectivity in
schizophrenia-tractography based segmentation of the corpus callosum.
Schizophr. Res. 106 (23), 125131.
Mitelman, S.A., Nikiforova, Y.K., Caneld, E.L., Hazlett, E.A., Brickman, A.M.,
Shihabuddin, L., Buchsbaum, M.S., 2009. A longitudinal study of the corpus
callosum in chronic schizophrenia. Schizophr. Res. 114 (13), 144153.
Molina, V., Sanz, J., Sarramea, F., Benito, C., Palomo, T., 2004. Lower prefrontal gray
matter volume in schizophrenia in chronic but not in rst episode
schizophrenia patients. Psychiatry Res. 131 (1), 4556.
Nakamura, K., Kawasaki, Y., Takahashi, T., Furuichi, A., Noguchi, K., Seto, H., Suzuki,
M., 2012. Reduced white matter fractional anisotropy and clinical symptoms in
schizophrenia: a voxel-based diffusion tensor imaging study. Psychiatry Res.
202 (3), 233238.
Navari, S., Dazzan, P., 2009. Do antipsychotic drugs affect brain structure? A
systematic and critical review of MRI ndings. Psychol. Med. 39 (11), 17631777.
Okada, N., Kasai, K., Takahashi, T., Suzuki, M., Hashimoto, R., Kameyama, T.,
Hiramatsu, K., Saito, O., Niwa, S., 2014. Rating scale of handedness for biological
psychiatry research among Japanese people. J. Biol. Psychiatry 25, 118119 (in
Japanese).
Rao, N.P., Venkatasubramanian, G., Arasappa, R., Gangadhar, B.N., 2011. Relationship
between corpus callosum abnormalities and schneiderian rst-rank symptoms
in antipsychotic-naive schizophrenia patients. J. Neuropsychiatry Clin.
Neurosci. 23 (2), 155162.

Reig, S., Parellada, M., Castro-Fornieles, J., Janssen, J., Moreno, D., Baeza, I., Bargall,
N., Gonzlez-Pinto, A., Graell, M., Ortuo, F., Otero, S., Arango, C., Desco, M., 2011.
Multicenter study of brain volume abnormalities in children and adolescentonset psychosis. Schizophr. Bull. 37 (6), 12701280.
Sowell, E.R., Peterson, B.S., Thompson, P.M., Welcome, S.E., Henkenius, A.L., Toga, A.
W., 2003. Mapping cortical change across the human life span. Nat. Neurosci. 6,
309315.
Tanaka-Arakawa, M.M., Matsui, M., Tanaka, C., Uematsu, A., Uda, S., Miura, K., Sakai,
T., Noguchi, K., 2015. Developmental changes in the corpus callosum from
infancy to early adulthood: a structural magnetic resonance imaging study.
PLoS One 10 (3), e0118760.
Thorup, A., Petersen, L., Jeppesen, P., Ohlenschlaeger, J., Christensen, T., Krarup, G.,
Jorgensen, P., Nordentoft, M., 2007. Gender differences in young adults with
rst-episode schizophrenia spectrum disorders at baseline in the Danish OPUS
study. J. Nerv. Ment. Dis. 195 (5), 396405.
Tibbo, P., Nopoulos, P., Arndt, S., Andreasen, N.C., 1998. Corpus callosum shape and
size in male patients with schizophrenia. Biol. Psychiatry 44 (6), 405412.
Venkatasubramanian, G., Jayakumar, P.N., Reddy, V.V., Reddy, U.S., Gangadhar, B.N.,
Keshavan, M.S., 2010. Corpus callosum decits in antipsychotic-nave
schizophrenia: evidence for neurodevelopmental pathogenesis. Psychiatry Res.
182 (2), 141145.
Venkatesh, B.K., Thirthalli, J., Naveen, M.N., Kishorekumar, K.V., Arunachala, U.,
Venkatasubramanian, G., Subbakrishna, D.K., Gangadhar, B.N., 2008. Sex
difference in age of onset of schizophrenia: ndings from a community-based
study in India. World Psychiatry 7 (3), 173176.
Walterfang, M., Wood, A.G., Reutens, D.C., Wood, S.J., Chen, J., Velakoulis, D.,
McGorry, P.D., Pantelis, C., 2008a. Morphology of the corpus callosum at
different stages of schizophrenia: cross-sectional study in rst-episode and
chronic illness. Br. J. Psychiatry 192 (6), 429434.
Walterfang, M., Yung, A., Wood, A.G., Reutens, D.C., Phillips, L., Wood, S.J., Chen, J.,
Velakoulis, D., McGorry, P.D., Pantelis, C., 2008b. Corpus callosum shape
alterations in individuals prior to the onset of psychosis. Schizophr. Res. 103 (1
3), 110.
Witelson, S.F., 1989. Hand and sex differences in the isthmus and genu of the human
corpus callosum. Brain 112 (3), 799835.
Woodruff, P.W., McManus, I.C., David, A.S., 1995. Meta-analysis of corpus callosum
size in schizophrenia. J. Neurol. Neurosurg. Psychiatry 58 (4), 457461.
Woodruff, P.W., Phillips, M.L., Rushe, T., Wright, I.C., Murray, R.M., David, A.S., 1997.
Corpus callosum size and inter-hemispheric function in schizophrenia.
Schizophr. Res. 23 (3), 189196.
World Health Organization, 1993. The ICD-10 Classication of Mental and
Behavioural Disorders: Diagnostic Criteria for Research. World Health
Organization, Geneva.