Department of Psychiatry, University Medical Centre Utrecht, The Netherlands
Correspondence: Dr W. Cahn, Department of Psychiatry, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Tel: +31 30 250 8180; fax: +31 30 250 5443; e-mail: w.cahn{at}azu.nl
* Presented in part at the European First Episode Schizophrenia Network
Meeting, Whistler BC, Canada, 27 April 2001.
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ABSTRACT |
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Aims To comprehensively investigate multiple brain structures in a single sample of patients who were antipsychotic-naïve.
Method Twenty antipsychotic-naïve patients with first-episode schizophrenia and 20 healthy comparison subjects were included. Intracranial, total brain, frontal lobe, grey and white matter, cerebellar, hippocampal, parahippocampal, thalamic, caudate nucleus and lateral and third ventricular volumes were measured. Repeated-measures analyses of (co)variance were conducted with intracranial volume as covariate.
Results Third ventricle volume enlargement was found in patients compared with the healthy subjects. No differences were found in other brain regions.
Conclusions These findings suggest that some brain abnormalities are present in the early stages of schizophrenia. Moreover, it suggests that brain abnormalities reported in patients with chronic schizophrenia develop in a later stage of the disease and/or are medication induced.
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INTRODUCTION |
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As evidence is accumulating that medication may alter brain structures (increases in basal ganglia volumes have been related to antipsychotic intake (Chakos et al, 1994; Keshavan et al, 1994; Scheepers et al, 2001) and decreases in frontal lobe volume have been related to the amount of antipsychotic medication used (Gur et al, 1998a; Madsen et al, 1998)), the study of brain morphology in antipsychotic-naïve patients with schizophrenia is crucial for an understanding of the disease. Studies comparing antipsychotic-naïve patients with first-episode schizophrenia with healthy comparison subjects have examined only one or a few brain structures (Table 1). These studies have inconsistently reported brain volume changes in antipsychotic-naïve patients with schizophrenia compared with healthy volunteers, which could be caused by factors such as a large variation in scanning acquisition and volumetric measures, inclusion of small numbers of subjects, inclusion of patients with a diagnosis other than schizophrenia and failure to match for age, gender, socio-economic class or handedness. In addition, some studies were not designed to exclusively compare antipsychotic-naïve patients with healthy comparison subjects.
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METHOD |
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Brain imaging
MRI acquisition
Magnetic resonance images (MRIs) were acquired on a Philips NT scanner
operating at 1.5 T. A T1-weighted three-dimensional fast field echo (3D-FFE:
echo time (TE)=4.6 ms, repetition time (TR)=30 ms, flip angle=30°, field
of view (FOV)=256/80% mm) with 160-180 contiguous coronal 1.2-mm slices, and a
T2-weighted dual echo turbo spin-echo (DTSE: TE1=14 ms, TE2=80 ms, TR=6350 ms,
flip angle=90°, FOV=256/80% mm) with 120 contiguous coronal 1.6-mm slices
of the whole head were used for the quantitative measurements. In addition, a
T2-weighted DTSE (TE1=9 ms, TE2=100 ms, TR=2200 ms, flip angle=90°,
FOV=250/100% mm) with 17 axial 5-mm slices and 1.2-mm gap of the whole head
was acquired for clinical neurodiagnostic evaluation. Processing was carried
out on the neuroimaging computer network of the Department of Psychiatry.
Before quantitative assessments, 10 images were randomly chosen and cloned for
interrater reliability purposes determined by the intraclass correlation
coefficient (ICC). All images were coded to ensure blindness for subject
identification and diagnosis, scans were entered into Talairach frame (no
scaling) (Talairach & Tournoux,
1988) and corrected for inhomogeneities in the magnetic field
(Sled et al,
1998).
Volume measurements
Intracranial, total brain, cerebral grey and white matter, lateral
ventricles and third ventricle and cerebellar volumes were measured
automatically by using histogram analysis algorithms and series of
mathematical morphological operators to connect all voxels of interest
(Schnack et al,
2001a,b).
Intracranial volume was segmented on the DTSE scans, with the foramen magnum
being used as inferior boundary. Total brain volumes were segmented on the
3D-FEE (T1-weighted) scans and contained grey and white matter tissue only. In
lateral ventricle segmentation automatic decision rules bridged connections
not detectable and prevented leaking into cisterns. The third
ventricle was limited by coronal slices, clearly showing the anterior and
posterior commissures; the upper boundary was a plane through the plexus
choroideus ventriculi tertii in the midsagittal slice perpendicular to this
slice. The cerebellum was limited by the tentorium cerebelli and the
brain-stem. All images were checked after the measurements and corrected
manually if necessary. The inter-rater reliability of the measurements
determined by the ICC based on 10 brains was 0.95 and higher. Segmentation of
the frontal lobe was performed automatically using the ANIMAL anatomical
segmentation algorithm (Collins et
al, 1994), which was validated previously for frontal lobe
volume measurements (Mandl et al,
1999).
Quantitative measurements of the caudate nucleus, thalamus, hippocampus and parahippocampus were obtained manually, from the 3D-FFE image using AnalyzeTM (Robb, 1995). The caudate nucleus was anteriorly defined in the first slice in which it was clearly visible. Its medial border was the lateral ventricle. Laterally, it was limited by the internal capsule, excluding the interconnecting grey matter striae between caudate and putamen visible in the internal capsule; posteriorly, by the last slice before the one in which the posterior commissure was clearly visible. Its inferior border was defined: anteriorly by the white matter connecting the rostrus corporis callosi and the capsula externa. Then, from the first slice where the putamen is clearly visible until the slice anterior to the slice in which the anterior commissure crosses the midline, the nucleus accumbens was separated by a line from the most inferior point of the lateral ventricle to the most inferior point of the internal capsule (adapted from Chakos et al, 1994). The thalamus was anteriorly defined in the first slice in which it was clearly visible, and precisely demarcated in the subsequent slices until the first slice after the coronal slice that included the posterior commissure. Its lateral border was defined by the internal capsule; its medial border by the third ventricle and its inferior boundary was defined by the anterior commissureposterior commissure plane. Segmentation of the hippocampus was started in the coronal slice in which the mammaillary bodies were visible and stopped when the fornix was visible as a continuous tract (adapted from Watson et al, 1992). Parahippocampal gyrus segmentation began in the coronal slice in which the optic tract is situated above the amygdala. The posterior commissure was its posterior border. Single operators performed the volume measurements of the above-named structures. The ICC for the left and right caudate nucleus was 0.98 and 0.99, for the thalamus, 0.77 and 0.86, for the hippocampus, 0.81 and 0.80 and for the parahippocampal gyrus, 0.77 and 0.75.
Statistical analyses
Repeated-measures analysis of covariance was conducted for total brain,
grey and white matter of the cerebrum (total brain, excluding cerebellum and
brainstem), frontal lobe, cerebellum, hippocampus, parahippocampus, thalamus,
caudate volumes and ventricles, with group (patients, healthy comparison
subjects) as the between-subjects variable and, if applicable, side (left,
right) and matter (grey, white) as the within-subjects variable. Intracranial
brain volume served as covariate for total brain, grey and white matter of the
cerebrum, cerebellar, lateral and third ventricle volume measures. Total brain
volume served as covariant for frontal lobe, hippocampal, parahippocampal,
thalamic and caudate volumes.
To examine associations between significant brain volume differences and
clinical variables (prodromal phase, duration of untreated psychosis, PANSS
scores) Pearson's correlations were calculated with intracranial volume as a
covariate. To assess the power of the study a power analysis, uncorrected for
intracranial volume, was carried out with a probability of 0.7 at an
level of 0.05.
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RESULTS |
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Mean (s.d.) volumes of total brain, frontal brain, grey matter, white matter, cerebellum, hippocampus, parahippocampus, thalamus, caudate nucleus, lateral ventricles and third ventricle are presented in Table 3 for patients and healthy comparison subjects.
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Intracranial volume and total brain measures
Intracranial volume (F=2.59, d.f.=1,38, P=0.12), total
brain volume (F=0.55, d.f.=1,37, P=0.47) and cerebral volume
(F=0.36, d.f.=1,37, P=0.56) did not differ significantly
between the two groups, nor was there a significant interaction effect of
group with matter (grey, white) of the cerebrum (F=0.21, d.f.=1,38,
P=0.65).
Frontal lobe and cerebellum
Frontal lobe volume (F=0.34, d.f.=1,37, P=0.56) and
cerebellar volume (F=0.34, d.f.=1,37, P=0.57) did not differ
significantly between the two groups.
Hippocampus, parahippocampus, thalamus and caudate nucleus
Hippocampus (F=0.11, d.f.=1,37, P=0.74), parahippocampus
(F=2.05, d.f.=1,37, P=0.16), thalamus (F=0.28,
d.f.=1,37, P=0.60), and caudate nucleus (F=1.23, d.f.=1,37,
P=0.27) did not differ significantly between the two groups.
Ventricles
Lateral ventricle volume (F=0.15, d.f.=1,37, P=0.70) did
not significantly differ between the two groups. However, third ventricle
volume was significantly larger in patients compared with the comparison
subjects (F=8.92, d.f.=1,37, P=0.005)
(Fig. 1).
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No significant interaction effects of group with matter or with side for any of these measures were found. No correlations were found between third ventricle volume and the clinical data. Excluding the patient with congenital hypothyroidism and her matched comparison subject did not alter the results.
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DISCUSSION |
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Third ventricle enlargement in antipsychotic-naïve patients with
schizophrenia
To our knowledge, third ventricle volume has not been examined with MRI in
patients with schizophrenia who were antipsychotic-naïve. Third ventricle
enlargement has been reported in studies of first-episode schizophrenia
examining mixed (antipsychotic-naïve and -treated subjects) samples of
patients (for review see Fannon et
al, 2000). A possible volume reduction in surrounding
diencephalic brain regions could explain the third ventricle enlargement,
although in our study this was not expressed in a reduction of thalamic
volume. The absence of a reduction in thalamic volume in our study is
consistent with the studies performed in anti-psychotic-naïve patients
with schizophrenia (Buchsbaum et
al, 1996; Gur et
al, 1998b). Interestingly, third ventricle
enlargement but also thalamic volume decrease were found in the healthy
siblings of patients with schizophrenia (Staal et al,
1998),
1999a;
Lawrie et al, 1999;
Seidman et al, 1999), suggesting that these findings could be related to a genetic vulnerability for
schizophrenia. The discrepancy of an increase of third ventricle without a
corresponding decrease in thalamic volume in this study might be related to
the relatively limited number of patients included, or could imply that other
regions in the proximity of the third ventricle, such as the hypothalamus, are
involved. Abnormalities in the hypothalamicpituitaryadrenal axis
have been suggested to be present in schizophrenia
(Tandon et al, 1991; Jansen et al, 2000;
Walder et al, 2000);
however, to date no study has been published measuring the hypothalamus in
schizophrenia.
No volume changes in brain tissue
This study found normal total brain and frontal lobe volume in
antipsychotic-naïve patients. This finding is inconsistent with the
findings by Gur et al
1998a,
2000b), demonstrating
total brain and frontal lobe reduction, specifically in prefrontal grey
matter, in antipsychotic-naïve patients with schizophrenia. In these
studies, however, a mixed sample of antipsychotic-naïve patients and
previously treated patients with schizophrenia was examined. Our finding of a
normal hippocampus in antipsychotic-naïve patients is congruent with the
only other MRI study (Laakso et
al, 2001) designed to examine hippocampal volumes in
antipsychotic-naïve patients compared with healthy comparison subjects.
Similar caudate nucleus volumes in both antipsychotic-naïve patients and
healthy comparison subjects have also been reported in one study
(Gur et al,
1998b), but not in others
(Keshavan et al,
1998a; Shihabuddin
et al, 1998; Corson
et al, 1999). The latter studies found reduced volumes in
patients. Differences in the various samples, such as diagnosis and
handedness, as well as variations in quantitative assessment techniques might
explain these inconsistencies.
Relative paucity of brain abnormalities
The relative paucity of brain abnormalities found in this study may
actually be the most striking finding. It stands in marked contrast with
findings in patients with more chronic schizophrenia, where volume reductions
in total brain and medial temporal lobe structures as well as volume
enlargement of lateral ventricles have been reported consistently (for review
see Wright et al,
2000). However, the most likely reason for this relative paucity
of brain abnormalities is a lack of power, as only 20 patients and 20 healthy
comparison subjects were included in this study. Several other explanations,
besides the lack of power, can be suggested to explain this discrepancy.
First, progression of the illness could lead to an increase of brain
abnormalities. A limited number of longitudinal studies in patients with
first-episode schizophrenia have been conducted suggesting that brain
abnormalities may indeed become more prominent over time
(DeLisi et al, 1997;
Gur et al,
1998a) at least in a subgroup of patients with poor
outcome (Lieberman et al,
2001). Second, medication might increase brain abnormalities and
could contribute to these brain volume changes as suggested by Gur et
al (1998a) and
Madsen et al (1998).
Third, finding few brain abnormalities in antipsychoticnaïve patients
could be the result of a selection bias favouring the inclusion of patients
who have a less severe form of schizophrenia. Two characteristics of our
sample, high education and a later age of onset, suggest it might indeed not
be representative of all patients with first-episode schizophrenia. In our
study no difference between patients and healthy comparison subjects on years
of education existed. A total of 9 patients of 20 had even completed part or
all of university training. In addition, their mean age at onset was at about
27 years. Interestingly, high education and a later age of onset are both
related to good outcome (Johnstone et
al, 1989; Weiselgren & Lindstrom, 1996), which in turn
appears to be associated with a relative lack of brain abnormalities at
presentation of illness (Staal et
al, 1999b). It has also been suggested that grey
matter volume is related to IQ (Andreasen
et al, 1993). Therefore, in this study a level of
education (and presumably premorbid IQ) similar in patients to that of the
healthy comparison subjects could have resulted in finding no decrements in
(regional) grey matter volume. Thus, although the relative paucity of brain
volume abnormalities in our sample could be indicative of progressive brain
changes in schizophrenia because of illness and/or medication, alternatively
it could have been the result of a selection bias that may be hard to avoid
when studying antipsychotic-naïve patients with schizophrenia.
Future studies
Although it may be practically impossible to determine whether brain
abnormalities in schizophrenia result from the progression of the illness
and/or medication, the suggestion of medication having an effect on brain
volume changes should be an incentive for future longitudinal studies to
carefully monitor medication intake.
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Clinical Implications and Limitations |
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LIMITATIONS
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