Department of Psychiatry, University of Turku, Turku University Central Hospital and Turku Psychiatric Clinic, Finland
Department of Psychology, University of California, Los Angeles, USA
Turku University Central Hospital, Finland
Turku Psychiatric Clinic and Department of Psychiatry, University of Turku, Finland
Department of Psychiatry, University of Turku, Finland
Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland
Department of Radiology, Turku University Central Hospital, Finland
Turku Psychiatric Clinic and Turku PET Centre, Turku Central Hospital, Finland
Correspondence: Raimo K. R. Salokangas, Professor of Psychiatry, TUCH, Psychiatry Clinic, FIN-20520 Turku, Finland. Tel: 358 2 3131 740; fax: 358 2 3132 730; e-mail: Raimo.K.R.Salokangas{at}tyks.fi
Funded by the Academy of Finland and Turku University Central Hospital.
* 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 study how regional brain volumes and their ratios differ between patients with schizophrenia, psychotic depression, severe non-psychotic depression and healthy controls.
Method Magnetic resonance imaging scans of the brain on first-episode patients and on healthy controls.
Results Patients with schizophrenia had a smaller left frontal grey matter volume than the other three groups. Patients with psychotic depression had larger ventricular and posterior sulcal cerebrospinal fluid (CSF) volumes than controls. Patients with depression had larger white matter volumes than the other patients.
Conclusions Left frontal lobe, especially its grey matter volume, seems to be specifically reduced in first-episode schizophrenia. Enlarged cerebral ventricles and sulcal CSF volumes are prevalent in psychotic depression. Preserved or expanded white matter is typical of non-psychotic depression.
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INTRODUCTION |
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Structural central nervous system abnormalities in schizophrenia and
affective disorders
Grey matter volume in patients with schizophrenia, in the neocortex
generally and in various subcortical structures, is fairly consistently
reduced, whereas the third and lateral ventricles, as well as the cortical
sulci, are enlarged (Pfefferbaum &
Marsh, 1995; Cannon,
1996; Buchanan & Carpenter,
1997; Lawrie & Abukmeil,
1998). In a recent meta-analysis, Wright et al
(2000) concluded that regional
structural differences in patients with schizophrenia include bilaterally
reduced volume of medial temporal lobe structures, consistent with a
pathological process in schizophrenia that involves distributed volume changes
within the brain.
In three meta-analyses, Elkis et al (1995) found that the ventricles and sulci were enlarged in patients with mood disorder compared with controls, and that ventricular enlargement was greater in patients with schizophrenia compared with those with mood disorders, although the effect size was small.
Crow (1990; Crow et al, 1996) suggested that brain changes in schizophrenia can be seen to include an arrest in the development of cerebral asymmetry. The normal asymmetry of the temporal horn (Crow et al, 1989a; Bogerts et al, 1990), the Sylvian fissure (Falkai et al, 1992; Crow et al, 1992), and volume in the occipital regions (Crow et al, 1989b; Daniel et al, 1989; Bilder et al, 1994) have been found to be absent in patients with schizophrenia in general, and in patients with first-episode schizophrenia specifically (Bogerts et al, 1990; Bilder et al, 1994; DeLisi et al, 1997).
Woodruff et al (1997) have reported that, in comparison with unaffected controls, male patients with schizophrenia demonstrated reduced correlations between several brain regions. The most salient abnormality in patients was the dissociation between prefrontal and superior temporal gyrus volumes, suggesting a lack of mutual trophic influences during frontal and temporal lobe development. These findings suggest the possibility that not only regional volumetric differences but also the interrelationships between regional structures can differentiate schizophrenia from other psychiatric disorders and healthy people.
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METHOD |
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The patients were selected from a larger group of first-contact patients admitted to out-patient or in-patient facilities of the Turku University Central Hospital and the Turku City Mental Health Centre, over a 41-month period (1 November 1994 to 31 March 1998). Inclusion criteria for the patients were: schizophrenia-spectrum psychotic disorder, bipolar disorder or severe major depression according to the treating clinician; first-ever psychiatric treatment in the public sector because of this disorder; age 16-64 years; and residence in the Turku City catchment area. The sample included 116 patients, 55 (47%) men and 61 (53%) women. Nineteen subjects (16%) were out-patients and 97 (84%) in-patients, and none of the subjects had been admitted to hospital before.
Patients meeting the inclusion criteria were interviewed by one of the research psychiatrists (T.T., H.K., H.L., K-M.L. and E.W.). Diagnostic interviews consisted of three parts: (a) taking of the patient's medical history using a structured form; (b) diagnostic evaluation using a clinical interview and a simultaneously recorded structured Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview (Wing et al, 1990); and (c) assessment of the severity of psychiatric symptoms by the Positive and Negative Syndrome Scale (PANSS; Kay et al, 1987), the Calgary Depression Scale (CDS; Addington et al, 1993), the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967), the Brief Psychiatric Rating Scale (BPRS; Overall & Gorham, 1962) and the Clinician Administered Rating Scale for Mania (CARS-M; Altman et al, 1994). The patients also underwent somatic investigations, including brain MRI and blood test scanning for somatic disorders with psychiatric symptoms.
The diagnostic evaluation was completed and the best-estimate research diagnoses according to DSM-IV (American Psychiatric Association, 1994) were made at consensus meetings, without any knowledge of the results of the MRI scans. At these meetings, all the patients' medical records and hospital charts were available, together with the findings of the previous diagnostic interview and somatic investigations. Patients' history and symptoms were discussed by the research psychiatrists responsible for the diagnostic evaluation, a senior researcher (R.K.R.S.), and at least one research psychiatrist not personally familiar with the patient. Particular emphasis was placed on making a distinction between schizophrenia and psychotic depression. On the basis of best-estimate research, the patients were divided into four main groups: schizophrenia (n=29); bipolar disorder (n=13); major depressive disorders (n=59); and others (n=15). The collection of patients and their investigations have been described in detail previously (Taiminen et al, 2000, 2001).
For this study, only patients with the DSM-IV criteria of schizophrenia (diagnoses 295.10, 295.20, 295.30, 295.60, 295.90), severe (with psychotic features) major depressive disorder (296.24, 296.34) and severe (without psychotic features) major depressive disorder (296.23, 296.33) with successful MRI scans were included. The study sample consisted of 11 patients with schizophrenia, 20 patients with depression with psychotic features and 17 patients with depression but not psychosis. In addition, 19 healthy volunteers were included in the analyses. At clinical interview, the healthy controls had no psychiatric disorder or neurological disease or symptoms, and their first-degree relatives had no major psychiatric disorder.
MRI scanning
Magnetic resonance imaging scans of the brain were acquired with a Siemens
1.5 T scanner (Siemens, Magnetom, Germany) in Turku University Central
Hospital. The scans were taken on average within 1.7 months of the clinical
examinations. A conventional dual spin-echo sequence (echo time of 90 ms,
repetition time 3120) was used to obtain on average 25 axial slices with a
thickness of 5.4 mm and no inter-slice gap. The image matrix size was 256
x 256 (field of view of 230) and an in-plane resolution of 0.9 x
0.9 mm.
Tracing protocol
The image analyses were performed using the NRIA (New Regional Image
Analysis) package, an earlier version of BBLImage. After deleting pixels
corresponding to the skull and meninges using a conservative automated
procedure followed by manual editing, the remaining pixels were classified
into three tissue types (grey matter, white matter and cerebrospinal fluid
(CSF)) using an adaptive Bayesian algorithm for three-dimensional tissue
segmentation (Yan et al, 1995). To control for head tilt during
scanning, the images were re-sliced according to the anterior
commissureposterior commissure plane. Detailed description of the
regions of interest (ROIs) can be found in Cannon et al
(1998). In short, the frontal
lobe ROI was started on the inferior slices, where the medial border was the
interhemispheric fissure and the lateral border the cortical perimeter. On the
slice superior to the mamillary bodies, the posterior border was defined by
extending a horizontal line from the most anterior extent of the Sylvian
fissure to the interhemispheric fissure. This posterior border was continued
in this fashion until the slice immediately preceding the splenium of the
corpus callosum. Superior to this slice, the posterior border was defined by a
horizontal line touching the most anterior part of the caudate nucleus. The
temporal lobe ROI was started at the level of the midbrain, where the
posteromedial border of the temporal lobe ROIs was delineated by the pons and
cerebellum. The temporal lobe was separated from the frontal regions by
tracing along the Sylvian fissure. More superior, the posterior boundary was
defined by drawing a line extending from the contralateral cerebral peduncle
to the anterior tip of the cerebellum. On the slices above the mamillary
bodies, the Sylvian fissure and the diencephalon structures served as the
medial borders. The posterior edge was formed by a horizontal line from the
most posterior tip of the posterior fossa to the lateral perimeter. The
temporal lobe ROI was discontinued on the first slice showing the splenium of
the corpus callosum. The posterior regions were defined by subtracting the
frontal and temporal lobe volume from the total brain volumes. The left and
right hemisphere ROIs included all brain tissue except pons, medulla, cerebral
peduncles and cerebellum. The ventricular ROIs included the lateral and third
ventricles but not the fourth ventricle or cerebral aqueduct. The anatomical
tracings were performed as described by a single rater with no knowledge of
the diagnosis. Interrater reliabilities of the defined measurements based on
10 randomly selected images were excellent (intraclass correlations,
0.93).
Statistics
Statistical analyses were performed with the SAS statistical software
package (SAS Institute, 1992).
Differences in distributions between subject groups were analysed by
chi-squared or MantelHaenszel chisquared test, and those in
continuously scaled variables by analysis of variance (ANOVA). The data of
tissue volumes were analysed with repeated-measures ANOVA and covariance
models. For analyses of grey matter, white matter and sulcal CSF, hemisphere
and region (frontal, temporal and posterior) served as within-subject
independent variables; for analyses of ventricular CSF, hemisphere was a
within-subject variable. In all models, overall intra-cranial volume and age
served as continuously scaled covariates, gender as a categorised covariate
and group (diagnosis) as a predictor. Multivariate analyses were followed by
pair-wise group contrasts using independent sample t statistics for
the sub-group (schizophrenia, psychotic depression, non-psychotic severe
depression and healthy controls) comparisons. The differences in tissue
volumes between patients and healthy controls are described in Figs
1,2,3,4
as Z scores, where the distances of values for patients from those for
controls were scaled by s.d. P values lower than 0.05 were considered
statistically significant and P values of 0.10-0.05 as marginally
significant.
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RESULTS |
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Regional volumes
Regional grey matter, white matter and CSF volumes are shown in
Table 2. In repeated-measures
ANOVA, intra-cranial volume had a significant effect (P < 0.05) on
all tissue volumes, and age on volumes of grey matter and sulcal and
ventricular CSF volumes. Diagnosis and region had a marginal interaction
(P=0.091) with grey matter volume and a significant interaction
(P=0.017) with sulcal CSF. Diagnosis, region and hemisphere had a
significant interaction (P=0.008) with white matter volume.
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When age, gender and intra-cranial volume were taken into account in ANOVA, there was a significant group effect in left frontal grey matter volumes (P=0.043), and a marginal group effect in right posterior sulcal CSF volumes (P=0.088).
In post hoc pair comparisons, patients with schizophrenia had a smaller left frontal grey matter volume than controls, patients with depression or psychotic depression. Moreover, their total frontal grey matter volume was significantly smaller than that of controls, and their posterior grey matter volume was larger than that of controls or patients with depression (Table 2 & Fig. 1). Patients with depression had marginally larger right frontal white matter volumes than controls. They also had larger white matter volumes than patients with schizophrenia or psychotic depression in several regions (Table 2 & Fig. 2).
Patients with schizophrenia had a marginally smaller left frontal sulcal CSF volume than controls. Patients with depression also had marginally smaller left frontal sulcal CSF and temporal sulcal CSF volumes than controls. Because of the large s.d., great differences of means remained marginally significant. Patients with psychotic depression had larger ventricular CSF volumes and larger posterior sulcal CSF volumes than controls. They also had larger ventricular CSF volumes than patients with schizophrenia and a larger posterior sulcal CSF volume and total sulcal CSF volume than patients with depression (Table 2 & Fig. 3).
Regional ratios
Contralateral ratios
In inter-hemispheric comparisons, left regional volumes were divided by
corresponding (contralateral) right volumes. This was called the contralateral
ratio. In repeated-measures ANOVA, age had a significant effect (P
< 0.05) on the contralateral ratio of volumes of grey and white matter,
whereas diagnosis had a marginally significant effect (P=0.079) on
the contralateral ratio of the volume of grey matter. Diagnosis and region had
a marginally significant interaction (P=0.066) with white matter
volume.
When the effects of age and gender were taken into account in ANOVA, there was a significant group (diagnosis) effect in the contralateral ratio of frontal grey matter (F=4.09, d.f.=3, P=0.011) and of posterior white matter (F=4.14, d.f.=3, P=0.010). In post hoc pair comparisons, when the effects of age and gender were taken into account, the contralateral ratio in patients with schizophrenia was significantly lower (i.e. left region was smaller in relation to right region) in frontal grey matter (-8.0%; F=10.2, d.f.=1, P=0.002), white matter (-9.2%; F=6.15, d.f.=1, P=0.013) and sulcal CSF volumes (-15.4; F=5.30, d.f.=1, P=0.025), and higher in posterior white matter volume (4.5%; F=4.31, d.f.=1, P=0.042) than in controls. Patients with depression had a marginally lower contralateral ratio in frontal grey matter (-4.1%; F=3.93, d.f.=1, P=0.052) and in frontal sulcal CSF (-10.8%; F=3.70, d.f.=1, P=0.059), as well as a significantly higher contralateral ratio in posterior white matter (5.5%; F=9.07, d.f.=1, P=0.004) than controls. Frontal grey matter contralateral ratio in patients with schizophrenia was lower (-7.4%; F=7.59, d.f.=1, P=0.008) than in patients with psychotic depression, whereas in patients with depression posterior white matter contralateral ratio was higher (4.8%; F=7.17, d.f.=1, P=0.010) than in patients with psychotic depression (Fig. 4).
Correlation coefficients were calculated between contralateral regional structural volumes. In general, the correlation between left and right corresponding regional volumes was high (r>0.800) and statistically significant (P <0.05). There was one exception: the correlation within frontal grey matter (r=0.413, P=0.207) was low in patients with schizophrenia, suggesting that, in schizophrenia, the contralateral inter-connection between frontal structures is rather weak.
Intra-hemispheric ratios
In intra-hemisphere comparison, frontal regional volumes were divided by
ipsilateral (same side) corresponding posterior and temporal volumes, and
temporal volumes by ipsilateral posterior volumes. This was called the
intra-hemispheric ratio. When the effects of age and gender were taken into
account, there was a significant group (diagnosis) effect in left grey matter
frontal posterior intra-hemispheric ratio (F=3.94, d.f.=3,
P=0.013), in left grey matter frontal temporal ratio
(F=3.56, d.f.=3, P=0.020) and in left sulcal CSF frontal
posterior ratio (F=5.11, d.f.=3, P=0.003).
In post hoc pair comparisons, when the effects of age and gender were taken into account, the left grey matter frontal posterior intra-hemispheric ratio (i.e. the rate of frontal grey matter divided by posterior grey matter) was lower in patients with schizophrenia than in controls (-14.6%; F=11.32, d.f.=1, P=0.001), patients with psychotic depression (-12.4; F=6.71, d.f.=1, P=0.012) and patients with depression (-13.2%; F=7.36, d.f.=1, P=0.009). The corresponding statistics for the left grey matter frontal temporal ratio were: patients with schizophrenia (-13.7%; F=9.21, d.f.=1, P=0.004), v. psychotic depression (-12.5%; F=7.70, d.f.=1, P=0.007) and v. patients with depression (-12.8%; F=7.70, d.f.=1, P=0.007). Compared with controls, the left sulcal CSF frontal posterior ratio was smaller in schizophrenia (-28.0%; F=10.08, d.f.=1, P=0.002), psychotic depression (-23.6%; F=11.21, d.f.=1, P=0.001) and depression (-19.1%; F=6.68, d.f.=1, P=0.012). Also the right sulcal CSF frontal posterior ratio was significantly lower in patients with psychotic depression than in controls (-20.3%; F=4.94; d.f.=1, P=0.030). No temporal posterior intra-hemispheric ratio values differed significantly between patients and controls.
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DISCUSSION |
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The findings of a meta-analysis (Wright et al, 2000) indicated that, in general, the frontal lobe reduction in schizophrenia is not extensive and is equally great on both sides. In the present study, frontal lobe reduction was rather extensive in the left frontal lobe. It is possible that changes in the brain volumes of patients with first-episode schizophrenia are more localised than those of chronic patients with a long duration of illness and drug treatment. J.H., T.C., T.v.E. and colleagues analysed regional brain volumes in never-medicated, first-episode patients and found reduced grey matter volumes in the left frontal and temporal lobe, as well as in the right posterior region, whereas differences in whole-brain grey volumes were non-significant (further details available from the author upon request). Prolonged treatments, social adversities and isolation may cause non-specific changes also in patients' cerebral structures and may explain the more extensive findings in the patients with chronic schizophrenia.
Interregional dissociation
We found a reduced inter-correlation between contralateral frontal grey
matter volumes in the patients with schizophrenia. Additionally, in these
patients, both the contralateral (left v. right) ratios of the
frontal grey and white matter volumes and the intra-hemispheric ratios between
left frontal and temporal grey matter volumes were smaller than those in
healthy controls or in the patients with depression. This result is in
accordance with the findings reported by Woodruff et al
(1997) that there is a
dissociation between frontal and temporal brain regions. According to the
findings of the present sample, this dissociation seems to be more pronounced
between left frontal lobe and other brain regions.
We did not measure asymmetry of the central nervous system directly. The reduced volume in the left frontal lobe of patients with schizophrenia may mean, however, that the structures of their left temporal lobe have had more space to move more anteriorally than those of healthy controls or other patients. This is in accordance with the finding that the auditory cortex of the temporal lobe was more anterior in the left than in the right hemisphere (Tiihonen et al, 1998). The lost asymmetry of the brain in schizophrenia, as suggested by Crow (1990; Crow et al, 1996), may therefore be a result of under-development of the left frontal lobe.
Enlarged ventricles in psychotic depression but not in
schizophrenia
In the present study, patients with psychotic depression had larger
ventricular CSF volumes than healthy controls. They also had larger posterior
sulcal CSF volumes than controls and patients with non-psychotic depression.
These findings are in accordance with several other studies. Most
consistently, patients with depression have shown enlarged lateral and third
ventricles, as well as sulcal enlargement
(Nasrallah et al,
1989; Elkis et al,
1995).
Contrary to several other studies which have shown that ventricular CSF volumes are larger in patients with schizophrenia than in healthy people (Weinberger, 1987; Elkis et al, 1995; Liddle, 1995; Lawrie & Abukmeil, 1998; Wright et al, 2000), even in patients with first-episode schizophrenia (Lim et al, 1996; Gur et al, 1999), in the present study, patients with schizophrenia did not have larger ventricular volumes. In fact, adjusted ventricular volumes were slightly smaller when intra-cranial volume was taken into account. We studied first-episode patients in the early phase of their illness; more than 10% of the patients were treated in out-patient care and the time lapse between examination and MRI scans was fairly short (on average, 1.7 months). It is thus possible that in the early stage of the onset of schizophrenia, grey matter reduction and changes in ventricular volumes are less prominent. In accordance with the present study, in their analysis J.H., T.C., T.v.E. and colleagues found no significant differences in ventricular volumes between never-medicated patients with first-episode schizophrenia and healthy controls (further details available from the author upon request).
Significance of differential diagnosis
One possible explanation for the structural differences between
schizophrenia and psychotic depression lies in diagnostic procedure. In the
present study, we concentrated on making differential diagnoses between
schizophrenia and psychotic depression, which are not always easy to
distinguish from each other. According to the DSMIV, a patient with
psychotic depression may have psychotic symptoms that are also often seen in
schizophrenia, and therefore, the presence of depressive state is important in
differentiating between psychotic depression and schizophrenia. On the other
hand, patients with schizophrenia often also have depressive symptoms, which
makes differential diagnosis difficult
(Martin et al, 1985).
We emphasised the presence of incoherence or clear disturbances in thinking
expressed in speech and a clear decline in functioning as important criteria
for schizophrenia.
An alternative explanation relates to the mean age of patients with schizophrenia in the present study: even though they were first-episode patients, mean age was rather high. A number of studies suggest that birth complications are associated with schizophrenia of severe type, male gender and early onset (McGrath & Murray, 1995), whereas, in the Copenhagen High Risk Study, large ventricles are associated with delivery complications in high-risk subjects (Cannon et al, 1993; Parnas, 1999). It is therefore possible that the patients with schizophrenia in the present study represent a selected group of individuals with fewer subcortical CNS defects, including enlargement of ventricles.
Independently of the diagnostic procedure, the patients in the present study were examined with a comprehensive neuropsychological test battery. These examinations showed that the patients with schizophrenia and psychotic depression performed more poorly than controls on several tests of the Wechsler Adult Intelligence Test Revised and Wechsler Memory Scale, but that the differences between these patients were not prominent (Ilonen et al, 2000a,b). However, a high score on the schizophrenia index (SCZI) developed by Exner (1993) was found in 70% of patients with schizophrenia, but in only 7% of patients with psychotic depression (Ilonen et al, 1999). The SCZI is related to disordered thinking and inaccurate perception. This finding supports the view that the pathognomonic thought disorders of schizophrenia could be related to frontal lobe (grey matter) deficiencies.
Thus, it is also possible that, because of the strict diagnostic procedure, the patients with schizophrenia in this study represent a less heterogeneous group of schizophrenias, with reduced grey matter mainly in the left frontal lobe, possibly because of genetic predisposition and associated with disturbances in cognitive performance (Zipursky et al, 1998; Gur et al, 1999), whereas the patients with psychotic depression seem to have enlarged CNS ventricles as well as reduced white matter volumes, possibly because of environmental damage. Indeed, the patients with psychotic depression had suffered more CNS damage than the patients in other diagnostic groups (Salokangas et al, 1998). This explanation is also in accordance with the findings of Cannon et al (1998). They proposed that cortical grey matter volume reduction in schizophrenia reflects a genetic predisposition, whereas ventricular enlargement reflects a primary non-shared causative effect, or is secondary to the illness or its treatment.
White matter reduction correlates with psychotic disorder
In the present study, the white matter volume differences between healthy
controls and the patients were rather extensive but, because of large standard
deviations, not significant. By contrast, the white matter volume differences
between patients with non-psychotic (depression) and psychotic disorders
(schizophrenia and psychotic depression) were more extensive, and the
interaction of diagnosis, region and hemisphere with white matter volume was
clearly significant. In general, patients with psychosis had smaller white
matter volumes than patients without psychosis. Thus, we propose that white
matter volume may be an important factor in the differential diagnosis of
psychotic and non-psychotic disorders in general, and between psychotic and
non-psychotic depression specifically.
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Clinical Implications and Limitations |
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LIMITATIONS
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