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Altered microstructure integrity of the amygdalain schizophrenia: a bimodal MRI and DWI study
B. Tomasino1, M. Bellani2, C. Perlini2, G. Rambaldelli2, R. Cerini3, M. Isola4, M. Balestrieri5, S. Calı2,
A. Versace2, R. Pozzi Mucelli3, A. Gasparini3, M. Tansella2 and P. Brambilla1,5*
1 Scientific Institute IRCCS ‘E. Medea ’, Udine, Italy2 Department of Public Health and Community Medicine, Section of Psychiatry and Clinical Psychology, Inter-University Centre for Behavioural
Neurosciences, University of Verona, Verona, Italy3 Department of Morphological and Biomedical Sciences, Section of Radiology, G.B. Rossi Hospital, University of Verona, Verona, Italy4 Department of Medical and Morphological Research, Section of Statistics, University of Udine, Udine, Italy5 Inter-University Centre for Behavioural Neurosciences, Department of Pathology and Experimental and Clinical Medicine, Section of Psychiatry,
University of Udine, Udine, Italy
Background. The amygdala plays a central role in the fronto-limbic network involved in the processing of emotions.
Structural and functional abnormalities of the amygdala have recently been found in schizophrenia, although there
are still contradictory results about its reduced or preserved volumes.
Method. In order to address these contradictory findings and to further elucidate the possibly underlying
pathophysiological process of the amygdala, we employed structural magnetic resonance imaging (MRI) and
diffusion weighted imaging (DWI), exploring amygdalar volume and microstructural changes in 69 patients with
schizophrenia and 72 matched healthy subjects, relating these indices to psychopathological measures.
Results. Measuring water diffusivity, the apparent diffusion coefficients (ADCs) for the right amygdala were found
to be significantly greater in patients with schizophrenia compared with healthy controls, with a trend for abnormally
reduced volumes. Also, significant correlations between mood symptoms and amygdalar volumes were found in
schizophrenia.
Conclusions. We therefore provide evidence that schizophrenia is associated with disrupted tissue organization of
the right amygdala, despite partially preserved size, which may ultimately lead to abnormal emotional processing in
schizophrenia. This result confirms the major role of the amygdala in the pathophysiology of schizophrenia and is
discussed with respect to amygdalar structural and functional abnormalities found in patients suffering from this
illness.
Received 8 May 2009 ; Revised 7 January 2010 ; Accepted 30 March 2010 ; First published online 12 May 2010
Key words : Apparent diffusion coefficient, brain, diffusion-weighted magnetic resonance imaging, magnetic resonance
imaging, morphometry, schizophrenia.
Introduction
The impaired ability to process emotion adequately,
such as affectivity, anxiety and fear, is one of the
most severe deficit in patients with schizophrenia
(Addington & Addington, 2000). Research done on
animal models (LeDoux, 1996, 2000 ; Davis & Whalen,
2001) and on humans (LaBar et al. 1995 ; Morris et al.
1998a, b ; Phelps et al. 2000 ; Adolphs et al. 2005)
supports the key role of the amygdala in fronto-limbic
circuitries involved in the modulation of human
emotions (LeDoux, 1998 ; Aggleton, 2000 ; Aggleton &
Young, 2000). Therefore, it is not surprising that dis-
turbances of the amygdala and its connections have
been implicated in the pathophysiology of schizo-
phrenia.
Patients with schizophrenia show functional ab-
normalities of amygdala activity (Kosaka et al. 2002 ;
Taylor et al. 2002; Takahashi et al. 2004 ; Williams et al.
2004 ; Fahim et al. 2005 ; Das et al. 2007) and an altered
functional connectivity in the amygdalar network
underlying fear perception (Keshavan et al. 2005 ; Das
et al. 2007 ; Leitman et al. 2008). Despite growing re-
search efforts, as to morphological changes, there are
still contradictory results about reduced or preserved
amygdalar volumes and structure in schizophrenia
(Altshuler et al. 2000; Niemann et al. 2000; Joyal et al.
* Address for correspondence : P. Brambilla, Dipartimento di
Patologia e Medicina Clinica e Sperimentale, Cattedra di Psichiatria,
AOU, P. le S. Maria della Misericordia 15, 33100 Udine, Italy.
(Email : paolo.brambilla@uniud.it)
Psychological Medicine (2011), 41, 301–311. f Cambridge University Press 2010doi:10.1017/S0033291710000875
ORIGINAL ARTICLE
2003). Indeed, there are some studies showing size
reductions (Nelson et al. 1998 ; Wright et al. 2000 ; Joyal
et al. 2003 ; Exner et al. 2004 ; Niu et al. 2004 ; Kalus et al.
2005 ; Namiki et al. 2007 ; Garcia-Marti et al. 2008) both
in chronic (Breier et al. 1992 ; Shenton et al. 1992 ; Marsh
et al. 1994 ; Anderson et al. 2002) and first-episode
patients (Hirayasu et al. 1998). A trimodal magnetic
resonance (MR) imaging (MRI) study (Kalus et al.
2005) detected a significant reduction of amygdala raw
volumes in 14 patients with schizophrenia, while
amygdala volumes normalized for intracranial volume
(ICV) did not differ between patients and controls.
In the same study, abnormally reduced diffusional
anisotropy and preserved magnetization transfer ratio
of the amygdala were found in individuals with
schizophrenia. On the contrary, other reports showed
no differences in amygdalar volumes between subjects
with schizophrenia and healthy controls (Altshuler
et al. 2000 ; Niemann et al. 2000 ; Staal et al. 2000 ; Levitt
et al. 2001 ; Szeszko et al. 2003; Tanskanen et al. 2005 ;
Velakoulis et al. 2006) and neither did a recent meta-
analysis study (Vita et al. 2006). Furthermore, there
is disagreement between a small number of post-
mortem studies investigating amygdalar volumes and
the number of neurones which did (Bogerts et al. 1985)
or did not (Heckers et al. 1990 ; Pakkenberg, 1990 ;
Chance et al. 2002) find significant differences between
patients with schizophrenia and normal controls.
A review of MRI studies showed that volume re-
duction involving the hippocampus, parahippo-
campal gyrus, or amygdala is reported in 77% of the
30 analysed studies (McCarley et al. 1999). A meta-
analysis revealed that a further source of variability
in results may depend on whether the amygdalar
volumes have been measured alone or in combination
with the hippocampus (Lawrie & Abukmeil, 1998).
In fact, out of 10 studies measuring the combined
amygdala and hippocampus, a 6% of reduction in the
median volume has been found, whereas out of six
studies measuring the amygdala separately the re-
duction was about 10% (Lawrie & Abukmeil, 1998).
Some studies report a decrease of amygdalar volumes
in individuals with schizophrenia bilaterally (Joyal
et al. 2003 ; Niu et al. 2004), in the right hemisphere only
(Pearlson et al. 1997) or in male patients only (Gur et al.
2000).
Based on the discrepancies of volumetric studies,
neuroimaging techniques that can provide infor-
mation about amygdalar microstructure organization
in schizophrenia would be of benefit. In the present
study, we further investigated amygdalar size and
cytoarchitectural integrity in a larger sample with re-
spect to the above-mentioned studies by combin-
ing structural MRI and diffusion weighted imaging
(DWI) techniques. In particular, MR design including
high-resolution volumetry and diffusion imaging
might provide a new strategy for the detection of
subtle structural alterations that cannot be visualized
by conventional volumetric imaging. Indeed, DWI
examines molecular water mobility within the local
tissue environment, providing important information
on tissue microstructural integrity. The diffusion of
water in the brain is characterized by its apparent
diffusion coefficient (ADC), which represents the
mean diffusivity of water along all directions (Taylor
et al. 2004). Thus, ADC gives potential information
about the size, orientation and tortuosity of both intra-
and extracellular spaces, providing evidence of dis-
ruption when increased (Rovaris et al. 2002). ADC has
also been used to explore regional grey matter micro-
structure, being higher in the case of potential neuron
density alterations or volume deficit (Sykova, 2004 ;
Ardekani et al. 2005 ; Ray et al. 2006).
Given that the deficit of processing emotion appro-
priately is a core symptom of schizophrenia and based
on previous literature showing a key role of the
amygdala in modulating human emotions, we ex-
pected that patients suffering from schizophrenia
would have an abnormally increased water diffusivity
of the amygdala compared with normal controls
resulting in greater ADCs, potentially without any
apparent gross abnormalities. In addition, the corre-
lations between clinical variables and amygdala
microstructure coherence were explored to investigate
whether the presence of abnormal water diffusivity
is also associated with particular psychopathological
dimensions, such as depression.
Method
Subjects
A total of 69 patients with schizophrenia according to
DSM-IV criteria [aged 40.46 (S.D.=12.06) years, 46
males] and 72 healthy control subjects [aged 40.13
(S.D.=11.09) years, 37 males] were studied (Table 1).
Patients were recruited from the geographically
defined catchment area of South Verona (i.e. 100 000
inhabitants) and were being treated by the South
Verona Community-based Mental Health Service
and by other clinics reporting to the South Verona
Psychiatric Care Register (Amaddeo et al. 2009 ;
Amaddeo & Tansella, 2009). Diagnoses for schizo-
phrenia were obtained using the Item Group Checklist
of the Schedule for Clinical Assessment in Neuro-
psychiatry (IGC-SCAN) (WHO, 1992) and confirmed
by the clinical consensus of two staff psychiatrists. The
IGC-SCAN was performed by two trained research
clinical psychologists with extensive experience in
the procedure. In fact, they administered at least
302 B. Tomasino et al.
10 IGC-SCANs with a senior investigator trained in
SCAN, after having conducted several IGC-SCANs.
Moreover, the psychopathological item groups com-
pleted by the two raters were compared, in order to
discuss any major symptom discrepancies. We also
ensured the reliability of the IGC-SCAN diagnoses
by holding regular consensus meetings with the psy-
chiatrists treating the patients and a senior investi-
gator. It is worth noting that the Italian version of the
SCAN was edited by our group (WHO, 1996) and that
our investigators attended specific training courses
held by official trainers in order to learn how to
administer the IGC-SCAN. Subsequently, diagnoses
for schizophrenia were corroborated by the clinical
consensus of two staff psychiatrists, according to the
DSM-IV criteria. Patients with co-morbid psychiatric
disorders, alcohol or substance abuse within the
6 months preceding the study, history of traumatic
head injury with loss of consciousness, epilepsy or
other neurological diseases were excluded. All but
one patient was receiving antipsychotic medications
at the time of scanning. Specifically, 25 were on typical
antipsychotic drugs (18 on haloperidol, four on flu-
phenazine, three on zuclopenthixol) and 43 on atypical
antipsychotic medication (23 olanzapine, 10 clozapine,
seven risperidone, three quetiapine). Of these subjects,
four were taking another antipsychotic at the time
of imaging (two clotiapine, one thioridazine, one
quetiapine). The mean chlorpromazine-equivalent
dose was 221.5 mg (see Table 1). Patients’ clinical in-
formation was retrieved from psychiatric interviews,
the attending psychiatrist and medical charts. Clinical
symptoms were characterized using the Brief Psy-
chiatric Rating Scale (BPRS, 24-item version; Ventura
et al. 2000), which was administered by two trained
research clinical psychologists. The reliability for the
BPRS was established and monitored utilizing pro-
cedures similar to the IGC-SCAN.
Healthy control subjects had no DSM-IV Axis I dis-
orders, as determined by a brief modified version of
the Structured Clinical Interview for DSM-IV, non-
patient version (SCID-NP), no history of psychiatric
disorders among first-degree relatives, no history of
alcohol or substance abuse and no current major
medical illness. Typical control subjects were hospital
or university staff volunteers or subjects undergoing
MR scans for dizziness without evidence of central
nervous system abnormalities on the scan, as de-
termined by the neuroradiologist (R.C.). Dizziness was
due to benign paroxysmal positional vertigo or to non-
toxic labyrinthitis. Control individuals were scanned
only after a full medical history had been taken,
general neurological, otoscopic, and physical exam-
inations carried out, and the patient had completely
Table 1. Sociodemographic and clinical variables for healthy controls and patients with schizophrenia
Healthy
controls (n=72)
Schizophrenia
patients (n=69) Statistics p
Age, years 40.13 (11.09) 40.46 (12.06) t=0.17 0.86
Gender (n) x2=3.40 0.07
Males 37 46
Females 35 23
Caucasian race (n) 72 69
Educational level, years 12.40 (4.19) 9.48 (3.31) t=x4.59 <0.01
Employment status (n) x2=16.27 <0.01
Employed 60 45
Unemployed 0 14
Student/housewife/retired 12 10
Age at onset (years) 26.61 (9.53)
Duration of illness (years) 14.11 (11.04)
Number of hospitalizations 4.30 (8.08)
Lifetime antipsychotic treatment (years) 12.06 (10.75)
BPRS depression–anxiety 12.65 (5.85)
BPRS negative symptoms 11.83 (5.27)
BPRS positive symptoms 11.58 (7.18)
BPRS manic excitement/disorganization 13.62 (7.44)
Mean CPZeq dose (mg) 221.5
BPRS, Brief Psychiatric Rating Scale ; CPZeq, chlorpromazine equivalent dose.
Values are given as mean and standard deviation or number of participants.
Amygdala microstructure in schizophrenia 303
recovered from the dizziness. In addition, none of
the control subjects was on medication at the time of
participation in the study, including drugs for nausea
or vertigo.
All participants gave signed informed consent, after
having understood all issues involved in participation
in the research, which was approved by the Bio-
medical Ethics Committee of the Azienda Ospedaliera
of Verona.
MRI acquisition
MRI scans were acquired with a 1.5T Siemens
Magnetom SymphonyMaestro Class, SyngoMR 2002B
(Siemans, USA). A standard head coil was used for
radio frequency transmission and reception of the
MR signal and restraining foam pads were utilized for
minimizing head motion. T1-weighted images were
first obtained to verify each subject’s head position and
image quality [TR=450 ms, echo time (TE)=14 ms,
flip angle=90x, field of view (FOV)=230r230, 18 slices,
slice thickness=5 mm, matrix size=384r512,
NEX=2]. PD/T2-weighted images were then acquired
(TR=2500 ms, TE=24/121 ms, flip angle=180x,
FOV=230r230, 20 slices, slice thickness=5 mm,
matrix size=410r512, NEX=2), according to an axial
plane parallel to the anterior-posterior commissures
(AC-PC), to exclude focal lesions. Subsequently, a
coronal three-dimensional magnetization-prepared
rapid gradient-echo (MP-RAGE) sequence was ac-
quired (TR=2060 ms, TE=3.9 ms, flip angle=15x,
FOV=176r235, slice thickness=1.25 mm, matrix
size=270r512, TI=1100) to obtain 144 images
covering the entire brain. Diffusion weighted echo-
planar images (EPIs) in the axial plane parallel to
the AC-PC line (TR=3200 ms, TE=94 ms, FOV=230r230, 20 slices, slice thickness=5 mmwith 1.5 mm
gap, matrix size=128r128, echo-train length=5;
these parameters were the same for b=0, b=1000, and
the ADC maps). Specifically, three gradients were
acquired in three orthogonal directions.
MRI data processing and analysis
Anatomical image analysis
Anatomical imaging data were transferred to a per-
sonal computer workstation and analysed using
the BRAINS2 software developed at the University
of Iowa (http://www.psychiatry.uiowa.edu/mhcrc/
IPLpages/BRAINS.htm). The amygdala was traced on
the T1-weighted (MP-RAGE sequence) images in the
coronal plane according to prior methods from our
group (Brambilla et al. 2003). All measurements were
done by a well-trained rater, who was blinded to
subject’s identity and achieved an inter-rater reliability
(IRR) of r=0.98 for the right amygdala raw volumes,
and r=0.91 for the left amygdala raw volumes, estab-
lished by blindly tracing 10 randomly selected scans
and calculated by intra-class correlation coefficient
(ICC). The volumes (ml) were obtained by summing
the volumes of all relevant slices and were expressed
in cm3. ICV was traced in the coronal place along the
border of the brain and included the cerebrospinal
fluid (CSF), dura mater, sinus, optic chiasma, brain-
stem, cerebral and cerebellar matter. The inferior
border did not extend below the base of the cerebel-
lum. ICV measurements were obtained by a well-
trained rater who achieved an IRR of 0.97 measured by
ICCs and established by blindly tracing 10 randomly
selected scans.
Diffusion image analysis
Images were displayed on a commercial Siemens
workstation for the post-processing analyses, includ-
ing the calculation of ADC values. ADC maps were
obtained from the diffusion images with b=1000, ac-
cording to the following equation:xbADC=ln [A(b)/
A(0)], where A(b) is the measured echo magnitude, b is
the measure of diffusion weighting and A(0) is the
echo magnitude without diffusion gradient applied
(Basser & Jones, 2002). The resulting ADC was ex-
pressed in units of 10x5 mm2/s. Circular regions of
interest (ROI) standardised at five pixels (corres-
ponding to an area of 0.16 cm2 and including five
pixels in total) were placed on both right and left
amygdala grey matter on the non-diffusion weighted
(b=0) EPIs. One axial slice below the mesencephalon
was chosen and adjacent slices were checked to ensure
that partial volume effects from CSF were minimized.
Then, the ROIs were automatically transferred to the
corresponding maps to obtain the ADC of water
molecules. Two raters achieved high reliability estab-
lished by tracing eight training scans, as defined by
ICCs over 0.80 calculated by taking into consideration
the mean ADC values. Then, the same rater, blind
to study hypotheses, group assignment, and socio-
demographic/clinical data, measured all scans.
Statistical analyses
SPSS for Windows software, version 17 (SPSS Inc.,
USA), was used to perform all statistical analyses, and
the two-tailed statistical significance level was set at
p<0.05. First, we compared demographic variables
using Student’s t test and Pearson’s x2, as appropriate.
A general linear model (GLM) for repeated measures
(hemisphere as repeated-measures factor) was used to
compare the volumes of amygdala between patients
304 B. Tomasino et al.
with schizophrenia and healthy control subjects with
age, gender and ICV as covariates. The same statistical
method (GLM for repeated measures, hemisphere as
repeated-measures factor) with the covariates age and
gender was performed to compare ADCs of amygdala
between the two groups. The assumption that the
vector of the measures followed a multivariate normal
distribution (Shapiro–Wilk test) and the variance–
covariance matrices were circular in form (Mauchly’s
test) were verified. Univariate GLM was performed to
compare the volumes and the ADCs of left and right
amygdala between patients with schizophrenia and
healthy control participants. The effect size, which is
the difference in the observed means divided by the
pooled standard deviation of the samples, was calcu-
lated for both volumes and ADCmeasurements. Effect
sizes are generally considered small if 0.2, medium if
0.5, and large if 0.8 (Cohen, 1988). Pearson’s corre-
lation and Spearman’s correlation analyses were used
to explore possible association between age and clini-
cal variables, respectively, and amygdalar volumes
and ADC measures. In this case the Bonferroni cor-
rection was used for multiple comparisons consider-
ing three clusters of correlations : chronological age,
clinical variables and scale measures.
Results
Volume and ADC measures
Left and right amygdala volumes did not signifi-
cantly differ between patients with schizophrenia
and healthy individuals [GLM for repeated measures,
hemisphere as repeated-measures factor and age,
gender and ICV as covariates : F(1, 136)=3.22, p=0.07,
observed power=0.43] (Fig. 1b). No interaction be-
tween group and hemisphere was found [F(1, 136)=0.47, p=0.49]. The left amygdala volumes did not
significantly differ between patients with schizo-
phrenia and healthy individuals [univariate GLM, age,
gender and ICV as covariates : F(1, 136)=2.2, p=0.13],
whereas a trend, which did not reach statistical
significance, was observed for the right amygdala
volumes, being smaller in patients in respect to con-
trol subjects [univariate GLM, age, gender and ICV as
covariates : F(1, 136)=3.56, p=0.06] (Table 2).
In regard to ADCs, patients with schizophrenia
had significantly greater ADC values compared with
healthy individuals [GLM for repeated measures,
hemisphere as repeated-measures factor and age and
gender as covariates : F(1, 137)=4.90, p=0.028, ob-
served power=0.59] (Fig. 1a). No interaction between
group and hemisphere was shown [F(1, 137)=0.63,
p=0.43]. Compared with the control group, patients
with schizophrenia had significantly greater values
for the right amygdala [univariate GLM, age and
gender as covariates : F(1, 137)=5.3, p=0.02], whereas
no significant differences were found for the left
amygdala [univariate GLM, age and gender as
covariates : F(1, 137)=2.23, p=0.13) (Table 2). Even
when educational level and occupation were con-
sidered as covariates the ADC values for the right
amygdala remained significantly reduced in patients
suffering from schizophrenia in comparison with
healthy controls (GLM for repeated measures,
p<0.05). Also, no significant differences were found
between the two control subgroups (GLM for repeated
measures, age and gender as covariates, p>0.05).
The calculated effect sizes in our present study were
medium to small for both volumes and ADC values
(Table 2).
Age and clinical variables
No correlation was found between age and amygdala
volumes either in the control group (left side : r=0.08,
95
90
85
80
75
AD
Cs
(mm
2 /s)
Left amygdala Right amygdala
2.0
1.5
1.0
0.5
0
Vol
ume
(cm
2 )
Left amygdala Right amygdala
(a) (b)
Fig. 1. Apparent diffusion coefficients (ADCs) (a) and volumes (b) of amygdala in patients with schizophrenia ( ) and normal
controls (%). Mean ADCs (mm2/s) and mean volumes (cm2) of the left and right amygdala are shown, with vertical bars
representing standard deviations.
Amygdala microstructure in schizophrenia 305
p=0.50 ; right side : r=0.05, p=0.66) or in the schizo-
phrenia group (left side : r=0.11, p=0.34 ; right side :
r=x0.004, p=0.96). Age was significantly correlated
with right amygdala ADC measures in the control
group (r=x0.27, p=0.019), but not in the schizo-
phrenia group (r=x0.19, p=0.11), although it did not
survive the Bonferroni correction (p>0.05). No sig-
nificant associations were found between age and left
amygdala ADCs in both controls (r=x0.14, p=0.22)
and patients (r=0.03, p=0.80).
No significant associations were found between
clinical features (age at illness onset, length of illness,
number of hospitalizations, antipsychotic lifetime
medication, chlorpromazine-equivalent dose) and any
of the anatomical or ADC measures (Spearman corre-
lation coefficients, p>0.05, after Bonferroni cor-
rection).
BPRS scores for depression–anxiety were sig-
nificantly directly correlated with both right and
left amygdalar volumes (r=0.45, p=0.0002 ; r=0.41,
p=0.001, respectively), even after Bonferroni correc-
tion (p=0.0008, p=0.004, respectively). Furthermore,
significant direct correlations were found between
BPRS scores for positive and mania/disorganization
symptoms and left amygdalar volumes (r=0.34,
p=0.008 ; r=0.33, p=0.009, respectively), even after
Bonferroni correction (p=0.032, p=0.036, respect-
ively).
Discussion
This MRI study showed that the ADCs for the right
amygdala were significantly greater in patients with
schizophrenia compared with healthy controls, with a
trend for significantly decreased volumes. By contrast,
left amygdalar size and ADC measures did not sig-
nificantly differ between groups. In this study we
combined the analyses of both amygdalar volumes
and microstructural organization in schizophrenia,
reporting a dissociation between altered integrity
of the right amygdala, as shown by increased ADC
values, and partially preserved volumes.
Microstructural integrity measures versus
volumetric imaging
Our results show that schizophrenia is associated
with an abnormally increased water diffusivity in the
right amygdala, suggesting that changes of amygdalar
tissue composition in schizophrenia may not necess-
arily affect the structural gross volume and should be
investigated at a cytoarchitectural level. DWI provides
evidence of tissue disruption even when conventional
volumetric quantification fails to detect size differ-
ences between patients and controls (DeLisi et al.
2006), being a complementary neuroimaging strategy
to structural imaging. In our study ROIs were placed
in the grey matter of the amygdala, being consistent
with the finding showing grey matter alterations in
schizophrenia (Wright et al. 1999 ; Steen et al. 2006).
ADC has been used by previous DWI studies to ex-
plore grey matter deficits, such as in patients with
traumatic brain injury (Hou et al. 2007 ; Galloway et al.
2008), obsessive–compulsive disorder (Nakamae et al.
2008) or schizophrenia (Shin et al. 2006). Furthermore,
it has been shown by MR spectroscopy (MRS) in-
vestigations that in healthy subjects N-acetyl aspartate
(NAA), a marker of neuronal integrity/functioning,
negatively correlates with ADC (Irwan et al. 2005).
Therefore, increased right amygdalar ADCs reported
in our study are consistent with reduced NAA in the
same region shown in MRS reports (Nasrallah et al.
1994).
Increased ADC values may probably reflect dis-
ruption of the composition of the extracellular inter-
neuronal space, which may cause an alteration in the
Table 2. Left and right amygdalar volumes and ADCs in healthy controls and patients with schizophreniaa
Healthy controls
(n=72)
Patients with
schizophrenia (n=69)
Statistics
F p Effect size
Left amygdala volume (cm3) 1.45 (0.28) 1.38 (0.29) 2.23 0.13 0.24
Right amygdala volume (cm3) 1.53 (0.29) 1.45 (0.31) 3.56 0.06 0.27
Left amygdala ADC (mm2/s) 81.54 (8.21) 83.37 (7.42) 2.23 0.13 0.23
Right amygdala ADC (mm2/s) 81.16 (6.73) 83.97 (9.24) 5.32 0.02 0.34
ADC, Apparent diffusion coefficient ; GLM, general linear model.
Values are given as mean (standard deviation).a GLM for repeated measures was performed to compare volumes (with age, gender and intracranial volume as covariates :
F=3.22, p=0.07) and ADC values (with age and gender as covariates : F=4.90, p=0.028) between patients with schizophrenia
and normal controls. In the Table the statistics of the univariate GLM are reported.
306 B. Tomasino et al.
neuronal and glial cross-talk mediated by neuro-
transmitters. Abnormalities of neurotransmission sys-
tems, such as dopamine, glutamate or c-amino butyric
acid, have strongly been suggested as the core of the
pathophysiology of schizophrenia. A model based on
the glutamate neurotransmitter hypothesis (Aleman &
Kahn, 2005) could explain amygdalar volume re-
ductions in patients with schizophrenia. Prolonged
hyperactivation of the amygdala during psychotic
states could lead to excessive glutamatergic activity
and excitotoxicity, resulting in amygdalar lesions and
long-term hypofunctioning (Hulshoff Pol et al. 2001).
However, what exactly an ADC increase is caused
by is still a matter of investigation, being both intra-
cellular and extracellular space sources of ADC. This
is indeed an average of water molecule diffusivity
within a selected ROI. Volume fraction alterations
of extracellular/intracellular spaces and changes of
neuronal cytoskeleton may therefore increase ADC
measurements (Sykova, 2004). In this perspective, our
findings may also suggest a reduced dendritic arbor-
ization, which has consistently been found in chronic
schizophrenia (Sweet et al. 2009). ADC may also be
used as a potential marker for alterations in neuron
density or for cortical volume deficit (Sykova, 2004 ;
Ardekani et al. 2005). In this regard, elevation of the
sulcal and ventricular CSF volume accompanies cor-
tical brain atrophy (Narr et al. 2003 ; Davis et al. 2004)
and results in a higher ADC. Therefore, increases
in ADC level may suggest replacement of brain
parenchyma by CSF, or volume loss. However, our
results partially match this view, because a disrupted
tissue organization of the right amygdala was found,
despite its partially preserved size. Moreover, a post-
mortem examination on amygdalar neuron number by
Pakkenberg (1990) showed no significant alteration in
subjects with schizophrenia, although only the baso-
lateral nucleus was included and not the whole region.
Right amygdala abnormalities may be involved
in the altered emotional processing in schizophrenia,
as supported by the correlations with affective symp-
toms. Our results are in line with the view propos-
ing that the right hemisphere hypersensitivity to
emotional material may play a crucial role for the
functional basis of schizophrenia (Oepen et al. 1987 ;
Kosaka et al. 2002 ; Exner et al. 2004). It should also be
noted that clinical variables (i.e. age at onset, length
of illness, number of hospitalizations) as well as anti-
psychotic treatment and dose did not apparently affect
amygdalar measurements. In this regard, there are
conflicting findings between studies reporting that
psychotropic medications might affect amygdala
size (Tebartz van Elst et al. 2004) and those suggesting
little influence of neuroleptics (Schneider et al. 1998 ;
Whittaker et al. 2001; Kosaka et al. 2002). Clearly,
studying unmedicated first-episode patients with
schizophrenia will provide a further opportunity
to assess whether microstructural abnormalities are
present prior to the administration of neuroleptic
treatment.
Correlation with psychopathological measures
Interestingly, significant direct correlations were
found between depression–anxiety, mania and posi-
tive symptoms and amygdalar volumes. Psycho-
pathology was measured by the BPRS, which was
divided into subscales in accordance with a prior
validated method (Ruggeri et al. 2005). Positive corre-
lations between amygdalar size and depression
severity have previously been reported in other dis-
eases, such as borderline personality disorder
(Zetzsche et al. 2006) and autism (Juranek et al. 2006). It
is of interest that amygdala dysfunction is implicated
in the development of depressive disorders (Drevets,
1998, 1999) as well as anxiety disorders (Birbaumer
et al. 1998; Garakani et al. 2006 ; Talarovicova et al.
2007). Altered amygdalar activation has been reported
in anxiety-prone subjects who had higher scores on
several measures assessing anxiety proneness (e.g.
neuroticism, trait anxiety and anxiety sensitivity)
(Stein et al. 2007). The association between amygdalar
volume and depressionn–anxiety symptoms suggests
that amygdalar abnormalities may be a predisposing
factor for increased stress sensitivity. Our findings
thus suggest that the amygdala plays a major role in
modulating emotions, including depressive, manic
and anxious symptoms, in schizophrenia and not only
in mood-related disorders. In this regard, it is of
interest to note that a prior diffusion tensor imaging
(DTI) study (Leitman et al. 2007) showed that reduced
fractional anisotropy of the amygdala contributes to
the inability of patients with schizophrenia in de-
coding emotional aspects of speech, which is crucial
for a preserved social communication (Bellani &
Brambilla, 2008 ; Bellani et al. 2009). Therefore,
emotions and anxiety should consistently be taken
into consideration by future imaging studies in
schizophrenia, which may potentially guide further
efforts towards developing treatment interventions for
alleviating affective symptoms.
Limitations of the study
First, in our study, although we recruited a large
number of patients, accurately matching them to con-
trol individuals in order to not increase variability,
we did not involve first-episode patients, our sample
being composed primarily by chronic treated patients.
Therefore, we cannot establish whether the amygdala
Amygdala microstructure in schizophrenia 307
disruption is present early in the course of the illness,
or whether it develops over time as a result of the
illness course or of psychotropic treatment. Second,
part of our control group was selected from individ-
uals undergoing MR scanning for dizziness, which
may represent a methodological limitation. However,
they were fully recovered at the time of imaging and
had no evidence of central nervous system abnor-
malities on the scan; auditory evoked potentials were
not investigated in these subjects. Future studies in-
volving larger samples of high-risk and first-episode
patients, as well as long-term follow-up studies, will
be needed to characterize whether abnormalities in
amygdala structure precede the appearance of symp-
toms, or appear afterwards, as a result of illness
course. Third, the diffusion images were not acquired
during cardiac gated imaging and the diffusion tensor
sequence (DTI) was not collected. However, both DWI
and DTI provide information on subtle tissue organ-
ization even when conventional structural MRI fails
to detect gross anatomical abnormalities (Basser &
Jones, 2002 ; Taylor et al. 2004). In this regard, our
DWI protocol, being relatively short, has the potential
to be added to any conventional volumetric scan,
representing a clinical and scientific advantage for the
evaluation of brain microstructure organization in
schizophrenia in the real world of psychiatric practice.
Conclusions
In conclusion, this study provides evidence of dis-
rupted amygdala cytoarchitecture in the right side, in
the presence of minimally preserved volumes, in a
large sample of patients with schizophrenia represen-
tative of those living in the geographically defined
catchment area of South Verona, Italy (i.e. 100 000 in-
habitants). Such abnormalities may result from a re-
duced microstructural integrity of this area or may
reflect a reduced dendritic arborization, ultimately
leading to abnormal emotional processing in schizo-
phrenia. This study thus confirms the role of the
amygdala in the pathophysiology of schizophrenia,
which may be related to microscopic alterations de-
tectable by the DWI technique added to any conven-
tional scan session.
Acknowledgements
This work was partly supported by grants from the
American Psychiatric Institute for Research and
Education (APIRE Young Minds in Psychiatry
Award), the Italian Ministry for Education, University
and Research (PRIN no. 2005068874), the Veneto
StartCup 2007 to P.B. and by a grant from Regione
Veneto, Italy (159/03, DGRV no. 4087).
Declaration of Interest
None.
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