NSERM CEA, Frédéric Joliot Hospital Department, Orsay
Albert Chenevier Hospital, Créteil, France
Department of Psychiatry and Psychobiology, University of Barcelona
Hospital Clinic i Provincial de Barcelona, Spain
Sainte-Anne Hospital, Paris
NSERM-CEA, Frédéric Joliot Hospital Department, Orsay, France
Correspondence: Jean-Luc Martinot, ERM 0205 Imagerie Cérébrale en Psychiatrie, INSERM-CEA, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 ORSAY Cedex, France. Tel: 1698 67719; fax: 1698 67816; e-mail: martinot{at}shfj.cea.fr
Declaration of interest The Fondation pour la Recherche Médicale supported J.-B.L.P.; D.B.-F. was supported by a post-doctoral grant from the Spanish Ministry of Education and Culture (MEC/Fulbright) and by an INSERM research fellowship.
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ABSTRACT |
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Aims To search for morphological anomalies of the PCS in men with early-onset schizophrenia.
Method The PCS was examined in magnetic resonance images of the brains of men with schizophrenia and 100 healthy men.
Results A significant asymmetry was found in the brains of healthy volunteers, whose sulci were more frequent and more marked in the left hemisphere. In contrast, the sulcus was as frequent in the right as in the left hemisphere in the patient group. Moreover, patients displayed significantly more rightward asymmetry, and overall less-asymmetrical patterns than the comparison group.
Conclusions Since the PCS has developed at 36 weeks of gestation, these findings suggest an impaired maturation of the cingulate region during the third trimester.
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INTRODUCTION |
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METHOD |
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Magnetic resonance imaging
Whole-brain T1-weighted images were acquired using a
1.5 T magnetic resonance imaging (MRI) scanner. A three-dimensional
inversion-recovery-prepared fast-spoiled gradient echo sequence was used with
the following scanning parameters: 256 x 256 matrix, 124 or 248
contiguous slices of 1.5-mm or 0.6-mm thickness, field of view 24 cm x
24 cm, flip angle 10°, echo time 2.2 ms, T1 600 ms,
repetition time 12.5 ms. Everyone who was scanned first gave written informed
consent, according to the local ethics committee requirements.
Paracingulate sulcus rating
The paracingulate sulcus extends dorsally and parallel to the cingulate
sulcus, lying in the medial walls of the frontal lobes. Measurements were made
using the method of describing paracingulate sulcus patterns defined by
Yücel et al
(2001) in healthy adults. The
origin of the paracingulate sulcus was defined as the point where the sulcus
extends posteriorly, from a coronal plane parallel to the line through the
anterior commissure, and perpendicular to the line through the anterior and
posterior commissures (Yücel et
al, 2001). The paracingulate sulcus was classified as
prominent if the sulcus extended at least 40 mm and exhibited no
more than 20 mm of interruptions between its origin and a coronal plane
passing through the anterior commissure
(Fig. 1c). If
interruptions exceeded 20 mm and the length was at least 20 mm, the
paracingulate sulcus was classified as present
(Fig. 1b). Finally,
when no clearly horizontal sulcus parallel to the cingulate sulcus could be
found or was less than 20 mm in length, it was classified as
absent (Fig.
1a). Leftward asymmetry was defined as a
prominent pattern in the left hemisphere with a
present or absent pattern in the right hemisphere,
or as present left and absent right patterns.
Conversely, rightward asymmetry was defined as a right prominent
pattern occurring with a left present or absent
pattern, or as a right present pattern and a left
absent pattern. Symmetry of the paracingulate sulcus was rated
when the same pattern was observed in both hemispheres. Two independent
raters, masked to participant status, examined the images. Intrarater
reliability was assessed by one examiner (J.-B.L.P.), who examined all cases
(=0.92). Interrater reliability was assessed by using a second rater
(D.B.-F.) to evaluate 70 randomly chosen participants (
=0.90).
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Intragroup asymmetry was assessed using McNemar's test for symmetry.
Hemispheric differences for paracingulate sulcus presence were assessed within
each group using 2 tests. Afterwards, between-group
differences for rightward/leftward asymmetry rates were also assessed using
2. Statistical significance was set at P=0.05.
Correlations between clinical scores and paracingulate sulcus patterns were
searched for in the patient group, using the Spearman rank order
statistic.
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RESULTS |
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Between-group comparisons
Paracingulate sulcus patterns (Table
1) were more often leftwardly asymmetric in healthy participants
than in patients (2=7.48, P=0.006). In contrast,
patients had more rightward asymmetric patterns (
2=4.84,
P=0.03). The incidence rates of a symmetrical pattern were similar in
both groups (
2=1.12, P=0.29).
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Clinical correlates
The presence or absence of paracingulate sulcus, either in the right or
left hemisphere, was not related to any clinical measure (SANS and SAPS
scores). Spearman correlation tests were applied to search for relationships
between asymmetry or symmetry of the paracingulate sulcus (leftward, rightward
or symmetrical) and clinical measures. No significant correlation was
observed.
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DISCUSSION |
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Patient characteristics
The characteristics of our patient sample (all men, with disease onset
before 25 years of age) may have influenced the findings. These patients were
chosen because previous studies have reported more-frequent brain anomalies in
early-onset cases (Crow et al,
1989b) and an interaction between diagnosis and gender on
frontal lobe measurements in patients with schizophrenia
(Highley et al,
1998). Moreover, previous investigations conducted in normal
individuals have found gender differences in paracingulate sulcus patterns, as
well as in intrasulcal paracingulate sulcus grey matter volumes
(Paus et al,
1996a; Yücel
et al, 2001). Therefore, it is possible that different
findings would be observed in older or female patients. Thus, it should be
stated that our results pertain to a homogeneous category of patients
(right-handed, male, with early-onset disease) and may not be generalisable to
other types of patient with schizophrenia.
Consistent replication
The finding of an asymmetric pattern of the paracingulate sulcus in healthy
individuals is consistent with previous anatomical MRI reports (Paus et
al,
1996a,b;
Yücel et al,
2001). Furthermore, our results replicate those reported by
Yücel et al
(2002a) and extend to
an independent sample of earlyonset cases, indicating that the reduction of
leftward paracingulate sulcus asymmetry might be a robust finding. They are
also complementary to reports of grey matter volume reductions in the
cingulate, suggesting an involvement of the cingulate and paracingulate region
in the pathophysiology of schizophrenic disorders
(Albanese et al, 1995; Wright et al, 1999;
Paillère-Martinot et al,
2001; Sigmundsson et
al, 2001). Further evidence implicating these limbic or
paralimbic regions in schizophrenia comes from functional findings
demonstrating abnormal brain activity in these regions in response to
cognitive demands (e.g. Carter et
al, 1997; Artiges et
al, 2000) and from a report showing that brain activity
patterns during a cognitive task depend on the underlying morphology of the
paracingulate sulcus (Yücel et
al, 2002b).
Folding and connectivity
Functional neuroimaging studies indicate that schizophrenia is
characterised by an alteration of brain connectivity (e.g.
Fletcher et al, 1999;
Spence et al, 2000).
Notably, it has been suggested that gyral-shape studies might be an
interesting alternative method of searching for disturbances of brain
connectivity in the disorder (Highley
et al, 2001). Indeed, brain gyrification indexes in
humans would reflect the density of intrinsic connectivity
(Welker, 1990). A proposed
mechanism derived from the tension-based morphogenesis theory explains
cortical folding as depending on differences in mechanical tension along
axons, dendrites or glial processes connecting different brain regions
(van Essen, 1997). Thus, the
presence of a prominent paracingulate sulcus could indicate a marked local
connectivity within the paralimbic cortex (Brodmann's area 32) and adjacent
regions (Brodmann's areas 6, 8 and 9). In contrast, the reduction in
paracingulate sulcus folding, more frequently observed in the left hemisphere
in our patients, could be the consequence of weaker local connectivity in
these areas. According to this model, people with sulcogyral anomalies would
be more likely to exhibit dysfunctional cingulate or paracingulate
connectivity.
Folding during the third trimester
It has been historically proposed that losses, absences or reversals of
hemispheric asymmetries could denote indexes of brain dysmaturation
(Crichton-Browne, 1879) in
mental disturbances (Southard,
1915). A corpus of theories postulate that the absence of right
shift (Annett, 1999) or the
loss of the physiological asymmetry in the ontogenetically recent heteromodal
cortices (Pearlson et al,
1996; Crow, 1999)
might result from genetic factors that would enhance the vulnerability to
schizophrenia. An anomaly in the paracingulate sulcus pattern in patients
supports these theories. Indeed, the paracingulate sulcus develops by 36 weeks
of gestation, when major cerebral asymmetry has already been established.
Thus, as a tertiary sulcus, it depends on the pattern of regional gyrification
previously established by primary and secondary sulci
(Armstrong et al,
1995). Consequently, evidence of altered paracingulate development
in people with schizophrenia may reflect abnormalities in the course of
neurodevelopment occurring, at the earliest, during week 32 of gestation, when
secondary sulci are forming i.e. during the third trimester. Folding
peculiarities in this paralimbic region during the third trimester do not
preclude more wide-spread and earlier anomalies in folding symmetry, which
remain to be investigated (Vogeley et al,
2000,
2001). Consequently,
sulcogyral measurements can be used to explore hypotheses (e.g.
Crow et al,
1989a; Bilder et
al, 1994) that disturbances in brain development during the
second and third trimesters are related to vulnerability to schizophrenic
disorders.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication January 24, 2002. Revision received August 21, 2002. Accepted for publication August 30, 2002.
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