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Araştırmalar / Original Papers
A Volumetric MRI Analysis of Hypochondriac Patients
Murad Atmaca1, Semih Sec2, Hanefi Yildirim3, Alperen Kayali4, Sevda Korkmaz2
ÖZET:
Hipokondriak hastalarda volümetrik MRG analizi
Hipokondriak hastalarda şu ana kadar gerçekleştirilmiş
volümetrik manyetik rezonans görüntüleme (MRG) çalışması bulunmamaktadır. Bu çalışmada, bu hasta grubunda
orbito-frontal korteks (OFK), anteriyor singulat, kaudat ve
talamus hacimlerini değerlendirmeyi amaçladık. Onaltı
hasta ve kontrolde OFK, anteriyor singulat, kaudat ve
talamus hacimleri T1-ağırlıklı koronal MRG imajları ile 1.5
mm kalınlıklı kesitlerle değerlendirildi. Hipokondriak hastalar daha küçük sol ve sağ OFK ve daha büyük sol talamus
hacimlerine sahipti. Kaudat ve anteriyor singulat hacimleri açısından gruplar arasında farklılık yoktu. Hamilton
Depresyon Ölçme Skalası (HDRS) skorları ölçülen herhangi
bir parametre ile ilişkili değildi. Hastalık başlangıç yaşı sol
ve sağ OFK ile ilişkiliydi. Hastalık süresi de sol OFK ve sol
talamusla anlamlı korelasyon gösterdi. Sonuç olarak, bu
morfometrik çalışma, hipokondriyazisli hastaların daha
küçük sol ve sağ OFK ve daha geniş sol talamus hacimlerine sahip olduğunu ortaya koymuştur. Bütün bunlar
sonucunda, bulgularımız OFK ve talamusun hipokondriyazis patofizyolojisinde önemli bir yere sahip olabileceğini
düşündürmektedir.
Anahtar sözcükler: MRG, Volümetrik, Hipokondriyazis,
Anteriyor singulat, OFK, Talamus, Kaudat
Kli­nik Psi­ko­far­ma­ko­lo­ji Bül­te­ni 2010;20:293-299
ABS­TRACT:
A volumetric MRI analysis of hypochondriac
patients
No volumetric brain magnetic resonance imaging (MRI) study
has been performed in hypochondriac patients to date. In
the present study, we aimed to volumetrically evaluate the
orbito-frontal cortex (OFC), anterior cingulate, caudate nucleus,
and thalamus. The volumes of the OFC, thalamus, caudate
nucleus, and anterior cingulate cortex were measured in
16 treatment-naive hypochondriac patients and 16 healthy
control subjects. Volumetric measurements were made with
T1-weighted coronal MRI images, with 1.5-mm-thick slices,
at 1.5T and were done blindly. Hypochondriac patients had
significantly smaller mean left and right OFC, and greater
left but not right thalamus volumes compared with healthy
controls. There was no difference in regard to caudate and
anterior cingulate volumes for either side between groups.
The Hamilton Depression Rating Scale (HDRS) scores were
not associated with any volumetric parameter studied. Age
at onset showed a significant relationship to left OFC, and
left thalamus volumes. Duration of illness also exhibited
a significant association with left OFC, and left thalamus
volumes. In conclusion, this morphometric MRI study showed
that patients with hypochondriasis had smaller left and right
OFC and significantly greater left thalamus volumes compared
to healthy controls. Taken together, our findings suggest that
abnormalities in the OFC and thalamus seem to play an
important role in the pathophysiology of hypochondriasis.
Key words: MRI, Volumetric, hypochondriasis, Anterior
cingulate, OFC, Thalamus, Caudate
Bulletin of Clinical Psychopharmacology 2010;20:293-299
INTRODUCTION
Hypochondriasis is defined as preoccupation with fears
of having, or the idea that one has, a serious disease based
on one’s misinterpretation of bodily symptoms. The main
characteristics of hypochondriasis are seeking repeated
physical examinations, diagnostic tests, and reassurance
from medical professionals; seeking reassurance from
friends and family about physical symptoms and doing
extensive research on the disease, my means such as using
the Internet or reading medical journals. Hypochondrasis
is currently classified as a somatoform disorder in DSMIV; however, it has some important similarities with
Professor of Psychiatry, 2Resident of
Psychiatry, Firat University School of Medicine
Department of Psychiatry, Elazig-Turkey
3
Associate Professor of Radiology, 4Resident of
Radiology, Firat University School of Medicine
Department of Radiology, Elazig-Turkey
1
Ya­zış­ma Ad­re­si / Add­ress rep­rint re­qu­ests to:
Murad Atmaca, M.D., Firat (Euphrates)
Universitesi, Firat Tip Merkezi Psikiyatri
Anabilim Dali, 23119 Elazig-Turkey
Telefon / Phone: +90-424-233-3555/2965
Faks / Faks: +90-424-238-8096
Elekt­ro­nik pos­ta ad­re­si / E-ma­il add­ress:
[email protected]
Ka­bul ta­ri­hi / Da­te of ac­cep­tan­ce:
12 Ekim 2010 / October 12, 2010
Bağıntı beyanı:
M.A., S.S., H.Y., A.K., S.K.: Yazarlar bu makale
ile ilgili olarak herhangi bir çıkar çatışması
bildirmemişlerdir.
Declaration of interest:
M.A., S.S., H.Y., A.K., S.K.: The authors reported
no conflict of interest related to this article.
obsessive–compulsive disorder (OCD), which is classified
as an anxiety disorder. OCD and hypochondriasis has
some similar features such as intrusive thoughts and
checking behaviors. On the other hand, hypochonriacal
concerns are thought to foster somatization (1,2). It has
been proposed hypochondriasis to belong to the obsessivecompulsive spectrum which consists of possible
phenomenpological and neurobiological disorders like
Tourette’s disorder, otistic disorder, somatoform disorders
such as body dysmorphic disorder and hypochondriasis,
and impulse control disorders (3-5).
Structural imaging studies of OCD, for example,
although not always consistent, have suggested basal
Klinik Psikofarmakoloji Bülteni, Cilt: 20, Sayı: 4, 2010 / Bulletin of Clinical Psychopharmacology, Vol: 20, N.: 4, 2010 - www.psikofarmakoloji.org
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A volumetric MRI analysis of hypochondriac patients
ganglia and frontal pathology (6,7). The findings from
structural imaging studies have been inconsistent, with
reports of increases (8), decreases (9,10) or no differences
(11-13) in the volumes of these key brain regions.
Recently, Pujol et al. (14) found reduced gray matter
volume in the medial frontal gyrus, the medial OFC, and
the left insulo-opercular region. In a very recent metaanalysis, Whiteside et al. (15) reported results that partially
support the conclusions drawn from previous narrative
reviews that point to structures in the OFC, caudate
nucleus, anterior cingulate, and thalamus as the key brain
regions in the pathophysiology of OCD. Functional
imaging studies have found altered activity in basal
ganglia and prefrontal areas at rest and during behavioral
challenge with feared stimuli in OCD patients (16). In a
recent study, we found that OCD patients had increased
white matter volume, significantly smaller left and right
OFC volumes and significantly greater left and right
thalamus volumes compared to healthy controls. Likewise,
in the same study, the patient group had anterior cingulate
exhibited a near-significant difference compared to healthy
controls on the left side. Previously, Kang et al. (17)
measured the volumes of the orbitofrontal cortex, anterior
cingulate gyrus, thalamus, and caudate nucleus, which are
the main components of the frontal subcortical circuitry in
patients with OCD and in normal subjects. These may be
key brain regions in the pathophysiology of OCD.
Functional MRI (fMRI) has been used to investigate
hypochondriasis. Van den Heuvel et al. (18) performed
voxel-wise analyses of cerebral blood flow changes for
contrasts of interest (incongruent vs. congruent color
words, OCD-related vs. neutral words, and panic-related
vs. neutral words) within and between OCD, panic
disorder, hypochondriasis, and control groups. Their
findings support the hypothesis of increased distractibility
by irrelevant information in patients with OCD, PD, and
hypochondriasis associated with frontal-striatal and limbic
involvement compared with controls. So far, no
hypochondriasis study has examined the OFC, anterior
cingulate, caudate nucleus, and thalamus concurrently in
hypochondriac patients. Accordingly, we decided to
perform a volumetric MRI study in hypochondriac
patients, visiting our clinic for the first time, focusing on
in vivo neuroanatomy of the whole brain, total gray and
white matter volume, thalamus, caudate nucleus, anterior
cingulate cortex, and the OFC concurrently.
294
MATERIALS AND METHODS
Subjects and clinical evaluations
The study group was retrospectively composed of
patients with hypochondriasis who applied to Firat
University School of Medicine Department of Psychiatry
directly or by referral to our department. A majority of
these patients had brain MRI investigation done for
severe headaches (n=8), and the remainder needed the
same investigation for a variety of other differential
diagnoses (e.g., meningitis, encephalitis, brain mass,
etcA total of sixteen patients and the same number of
healthy controls were studied. Diagnoses were made
according to the Diagnostic and Statistical Manual of
Mental Disorders Fourth Edition (DSM-IV) and the
Structured Clinical Interview for the Diagnostic Schedule
for Mental Disorders-Fourth Edition (SCID) (19).
Severity of depressive symptoms was assessed with the
Hamilton Depression Rating Scale (HDRS) (20). Healthy
controls were matched on age, sex, education and
handedness.
Patients with any current comorbid psychiatric
disorder, current or lifetime neurological disorders,
current medical problems, history of head trauma, and
alcohol/substance abuse within the 6 months preceding
the study were excluded. With respect to comorbidity in
the patient group, as assessed by the SCID and clinical
interviews, none met criteria for any current psychiatric
disorder. Additional comorbid lifetime Axis I psychiatric
diagnoses were major depressive disorder (n=1), and
panic disorder (n=1). Healthy control subjects had no
DSM-IV Axis I disorders in themselves or in a firstdegree relatives, as determined by the SCID non-patient
version, no current medical problems, neurological or
psychiatric histories, and no use of psychoactive
medications within 2 weeks of the study. None of the
controls had taken any psychotropic agents. In the patient
group, the father of one patient had a current diagnosis of
panic disorder and the mothers of two patients had
histories of OCD and depressive disorder.
There were no significant group differences in age,
years of education, and sex and handedness ratios.
The procedures followed were in accordance with the
Helsinki Declaration of 1975, as revised in 1983.
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M. Atmaca, S. Sec, H. Yildirim, A. Kayali, S. Korkmaz
MRI Procedure
MRI were acquired with a 1.5-Tesla GE signa Excite
high speed scanner (Milwakuee, USA). A high-resolution
structural image of the entire brain was obtained using
sagittally acquired 3D spiral fast spin echo high-resolution
images (repetition time [TR]=2000 ms, echo time
[TE]=15.6 ms, field of view [FOV]=240 mm, flip
angle=200, bandwidth=20.8, slice thickness=2.4 mm,
echo spacing=15.6 ms, 8 echoes, matrix size=240,
resolution=0.9375×0.9375×2.4 mm).
Anatomic measurements were obtained on a computer
advanced workstation with the GE Volume Viewer
voxtool 4.2 program. Tracing was performed by one
researcher (HY) blind to the diagnoses of the subjects, and
independently verified by a second (HO) blinded
investigator. Measured brain structures consisted of the
whole brain, total gray and white matter volumes,
thalamus, caudate nucleus, anterior cingulate cortex, and
the OFC. The boundaries of structures evaluated were
delineated on the coronal MR images according to
standard brain atlases (21-23) and were adapted from
Noga et al. (24), Portas et al. (25), Lacerda et al. (26),
Sassi et al. (27), and Riffkin et al. (13):
Caudate. For the tracing of caudate nucleus, posterior
border was determined as pontine cistern. The posterior
landmark was represented by the pontine cistern. The
lateral ventricle and the internal capsule were the medial
and lateral boundaries, respectively. The most anterior
boundary was identified using the mammillary bodies of
the hypothalamus as a landmark.
Thalamus. The anterior boundary was defined as the
mammillary bodies and interventricular foramen. The
posterior boundary was the point merging the thalamus
Figure 1: Anatomic landmarks for the tracing of the structures evaluated
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A volumetric MRI analysis of hypochondriac patients
under the crus fornix. The lateral boundary was the
internal capsule while the third ventricle was determined
as the medial boundary. The inferior and superior
boundaries were the hypothalamus and the lateral
ventricle, respectively.
OFC. The last slice traced was the most anterior
coronal slice where brain tissue could be identified. For
the tracing procedure for measuring the OFC, the posterior
boundary was established where the olfactory sulcus was
just visible. The posterior boundary was established
where the olfactory sulcus was just visible. While the
inferior boundary was accepted by the most inferior
aspect of the cortex, the lateral boundary was defined by
the most lateral edge of the cortex. The medial boundary
was the longitudinal fissure.
Anterior cingulate. For the tracing procedure for
measuring the anterior cingulate, the cingulate sulcus
defined the upper limit and the callosal sulcus the lower
limit of the cingulate gyrus. The tracing was continued
until the slice where the anterior commissure was most
visible. The posterior boundary was the anterior
commissure. Examples of the structures of coronal slices
are presented in Fig 1. All volumes were reported in cubic
centimeters. For ICV, whole brain, total gray and white
matter volumes, the interrater reliability (intraclass
correlation coefficient [ICC]), established by tracings of
two different evaluators, was found to be high, ranging
between 0.88 and 0.94. ICC’s were 0.86 and 0.86 for left
and right OFC, 0.82 and 0.85 for left and right ACC, 0.88
and 0.96 for left and right thalamus and 0.86 and 0.86 for
left and right caudate nucleus, respectively.
Statistical Analysis
Analysis of covariance (ANCOVA), t test, and partial
correlation analyses were conducted using SPSS for
Windows software, version 10.0 (SPSS, Chicago, IL). In
ANCOVA analyses, age and whole brain volumes were
covariates. Correlation analyses were done by using
Spearman’s rank test. Statistical significance was defined
as P<0.05 by a two-tailed t-test.
RESULTS
No significant difference was found in demographic
variables of age, gender composition, educational level,
and intracranial volume (ICV) between hypochondriac
patient (1432.3±134.8) and healthy control groups
(1456.9±152.1) (t=0.959; P>0.05). In the patient group,
HDRS scores were 14.5±4.1 (Table 1).
Whole brain volume, white and gray matter volumes
did not differ between patients and healthy controls
(P>0.05). Hypochondriac patients had significantly
smaller mean left (t=6.21; P<0.001) and right (t=3.45;
P<0.01) OFC, and greater left (t=4.72; P<0.001) but not
right (t=1.35; P>0.05) thalamus volumes compared with
healthy controls. There was no difference in regard to
caudate and anterior cingulate volumes for both sides
between groups (P>0.05).
Whole brain volume, white and gray matter volumes
did not differ between patients and healthy controls after
covarying for age (P>0.05). The OFC volumes remained
significantly smaller in the patients after covarying for
whole brain volume and age. Specifically, the repeated
measures ANCOVA predicting left and right OFC
volumes detected a significant main effect of diagnostic
group (P=0.034). After covarying for whole brain volume,
a statistically significant difference still remained between
patients and healthy controls (P=0.039) in regard to left
thalamus.
The HDRS scores were not associated with any
volumetric parameter studied. Age at onset showed a
Tab­le 1: Clinical and demographic characteristics
Item
Patients group (n=16)
Control group (n=16)
Age (years)
30.4±4.2
26.8±3.1
Gender (Female/Male)
7/9
8/8
Education High school
High school
7
7
Elemantary school
3
2
First school
2
3
Handedness (right)
16
16
Length of illness (months)
5.9±3.3
-
Hamilton Depression Rating Score
13.8±4.7
-
296
p
>0.05
>0.05
>0.05
>0.05
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M. Atmaca, S. Sec, H. Yildirim, A. Kayali, S. Korkmaz
Tab­le 2: The Volumes of the Structures Evaluated in Patients versus Controls (Mean ± Standard Error)
Patients (n=16)
Healthy Controls (n=16)
t
Whole Brain Volume
1331.45±172.62
1294.67±142.9
1.30
Gray Matter Volume
804.53±91.4
779.64±78.3
1.42
White Matter Volume
526.89±68.57
515.03±55.23
1.19
OFC Volumes
Left
10.22±2.31
15.76±2.72
6.15
Right
11.12±2.87
14.94±3.34
5.94
Anterior Cingulate Volumes
Left
1.79±0.30 1.67±0.28
0.71
Right
1.90±0.22
1.86±0.57
0.26
Caudate Volumes
Left
3.52±0.62
3.78±0.44
1.41
Right
3.98±0.68
3.66±0.91
1.10
Thalamus Volumes
Left
6.56±0.68
5.33±0.78
4.72
Right
6.12±11.76
5.83±1.23
1.35
p
>0.05
>0.05
>0.05
<0.001
<0.01
>0.05
>0.05
>0.05
>0.05
<0.001
>0.05
Volumes presented are in cm3.
significant relation with left OFC (r=0.42, P=0.023), and
left thalamus volumes (r=-0.36, P=0.038). Duration of
illness also exhibited a significant association with left
OFC (r=-0.51, P=0.012), and significant relation with left
thalamus volumes (r=0.48, P=0.017).
DISCUSSION
Before embarking on the interpretation of these
interesting results, we want to emphasize some important
findings. The present study found a significant reduction
of left and right OFC and significantly greater left
thalamus volumes of hypochondriac patients compared to
healthy controls. In addition, while age at onset showed a
significant relation with left OFC and left thalamus
volumes, duration of illness also exhibited a significant
association with left OFC, and significant relation with
left thalamus volumes. To our knowledge, this is the first
report of volumetric MRI investigation in patients with
hypochondriasis. This is a critical demonstration, as it has
not been previously known whether any brain volume
abnormalities exist in hypochondriasis. Of particular note
is the fact that these findings were obtained in a sample of
patients with a “pure” hypochondriasis, i.e., without any
past or current major psychiatric comorbidity with the
exception of major depressive disorder (n=1), and panic
disorder (n=1). Another important feature of the study
was the close matching between each patient and a
healthy comparison subject, which minimized possible
confounding factors such as gender composition,
educational level, and age. One of the main psychiatric
conditions associated with abonormalities of theOFC
which is evaluated in the present study is OCD. Szeszko
et al. (8) reported that patients with OCD had significantly
reduced bilateral OFC volumes as compared with healthy
subjects by using MRI. In Pujol et al.’s study (14), the
brains of patients with OCD showed reduced gray matter
volume in the medial frontal gyrus, the medial orbitofrontal
cortex, and the left insulo-opercular region. In addition,
there is evidence of activity changes in the OFC in OCD.
Functional neuroimaging studies, which have compared
OCD patients with controls, reported inconsistent results
on anterior cingulate and caudate abnormalities in OCD,
while relatively more consistent findings have been
reported on abnormalities of the the OFC in OCD patients
(28). Several authors (3) have proposed that
hypochondriasis may belong to the “obsessive–compulsive
spectrum” which is a group of disorders that share several
features with OCD, including symptoms, sex ratio, course,
comorbidity, and neurobiological and neuroanatomical
associations although this spectrum can be defined in
various ways. Moreover, in the present study, we found
that hypochondriac patients had significantly smaller left
and right OFC volumes compared to healthy controls.
These results are in accordance with, not only the findings
of the mentioned studies, but also the conceptualization
that hypochondriasis may be an obsessive–compulsive
spectrum disorder.
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A volumetric MRI analysis of hypochondriac patients
There is no systematic investigation evaluating
thalamic volumes in hypochondriasis. In only one case
report, it has been reported that hypochondriac complaints
including long-standing hysterical pain and visceral
disturbances were successfully treated by unilateral
anterior thalamotomy (29). The fact that partial
thalamotomy could reduce symptom severity in treatmentrefractory OCD patients (30) provides further evidence on
its role of pathophysiology of OCD. In our previous study,
we have found that patients with OCD have significantly
greater left and right thalamus volumes compared with
healthy controls. Overall, we may say that hypochondriac
patients behave as OCD patients in regard to brain
abnormalities in pathophysiology.
In the present study, we did not find any differences in
regard to anterior cingulate and caudate volumes. No
study has examined the role of these areas in hpochondriasis
until now. The reason why we evaluated these areas in
hypochondriac patients was to determine whether
hypochondriasis has similar brain morphometric
abnormalities to OCD since the OFC and thalamus are
also key brain regions in OCD (11,13,31,32). We suggest
that hypochondriasis and OCD seem to share some
morphometric differences although they have some
morphometric similarities.
While age at onset showed a significant relation to left
OFC and left thalamus volumes, duration of illness also
exhibited a significant association with left OFC, and left
thalamus volumes. This finding suggests that OFC and
thalamus abnormalities may be present at the early stages
of the illness, supporting the notion of progressive brain
structural changes subsequent to the onset of
hypochondriasis. The design of our study does not allow
us to establish either the time of onset or the mechanisms
of the changes in areas evaluated in hypochondriac
patients. In fact, these marked changes may well originate
from early developmental processes such as abnormal
synaptic arborization or myelination (or may have nothing
to do with gray matter at all and be restricted to white
matter) or, rather, suggest some kind of neuronal damage
that would involve the amygdala, but not the hippocampus.
There are several important limitations of this study
that should not be overlooked or underestimated. First, the
number of subjects is small especially given the condition.
To be able to generalize these results, replication of the
current findings is essential. Second, as we acknowledged,
the statistical threshold applied is somewhat liberal,
further underscoring the need for replication. Third, we
did not perform a segmentation for anterior cingulate and
OFC volumes. Fourth, other limitations including the lack
of consideration of the effects of IQ should be mentioned.
The fifth limitation is the lack of segmentation of gray
versus white matter in OFC and the anterior cingulate. In
addition, it is unfortunate that we did not use any rating
scale for hypochondriac symptoms. In future studies,
rating scales should be used for assessment of
hypochondriac symptoms.
In conclusion, this morphometric MRI study of
hypochondriac patients shows that hypochondriac patients
had smaller left and right OFC and significantly greater
left thalamus volumes compared to healthy controls.
Taken together, our findings suggest that abnormalities in
the OFC and thalamus seem to play an important role in
the pathophysiology of hypochondriasis.
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