Highfield Adolescent Unit, Warneford Hospital, Oxford
Unidad de Salud Mental Infantil, Centro de Salud Hospital Provincial, Alicante, Spain
Highfield Adolescent Unit, Warneford Hospital, Oxford
Centre for Statistics in Medicine, Institute of Health Sciences, Headington, Oxford
Correspondence: A. C. D. James, Highfield Adolescent Unit, Warneford Hospital, Warneford Lane, Headington, Oxford OX3 7JX, UK
Declaration of interest Funding provided by Oxfordshire Regional Health Authority and SANE.
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ABSTRACT |
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Aims To investigate the hypothesis that structural brain abnormalities in adolescent-onset schizophrenia are progressive in the early phase of the illness.
Method A magnetic resonance imaging casecontrol study of 16 adolescents with schizophrenia (mean age 16.6 years, s.d.=1.9 years) with a mean time of 2.7 years (s.d.=1.7 years) between measurements and 16 matched controls (average age 16.0 years, s.d.=2.0 years) with a mean time of 1.7 years (s.d.=0.5 years) between measurements.
Results There was no evidence of progressive structural brain changes during late adolescence. Significant ventricular enlargement (greater in males) and left-sided temporal lobe changes were evident from the outset of the illness.
Conclusions Neurodevelopmental brain abnormalities are non-progressive during late adolescence.
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INTRODUCTION |
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METHOD |
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The patients were a severely ill group but they were compliant with medication throughout the study period. The majority received typical neuroleptics at the onset of the study; although most were transferred to atypical neuroleptics, three were treatment resistant and on clozapine.
Magnetic resonance imaging
Subjects were scanned on a General Electric Signa 1.5 Tesla MRI machine,
which remained the same throughout the study with regular quality control
checks. The chin was elevated so that the volumetric gradient echo sequence
(which cannot be angled) was perpendicular to the temporal lobe, to minimise
partial volume effects. The initial two scans were to ensure correct patient
orientation the anterior genu of the corpus callosum and the clivus
should follow a vertical line. These sequences were repeated if necessary to
ensure a horizontal anterior commissureposterior commissure (AC-PC)
line. Image sequences were as follows:
Anatomical markers
The temporal lobe was defined posteriorly at the level where all four
colliculi were visualised. Temporal lobe and medial temporal lobe structures
were measured manually on sequential coronal slices. The temporal stem was
demarcated by a line connecting the most inferior point of the insular
cisterns to the most lateral point of the basal cisterns above the
hippocampus. Medially, the boundary between the temporal lobe and cerebrum was
determined by drawing a perpendicular line from the most inferior aspect of
the Sylvian fissure across the narrowest portion of the temporal lobe. The
hippocampus and amygdala were outlined using a manual tracing method. The
hippocampus was defined posteriorly by the separation of the crus of the
fornix from the hippocampus, and anteriorly from the head of the amygdala by
the uncal recess of the inferior horn of the lateral ventricle. The anterior
amygdala was measured only in those slices where the grey matter was 2.5 times
the thickness of the adjacent cortical grey matter. Images were displayed in
three-dimensional orthogonal views using the RESCUE program
(Griffin et al,
1994). A hierarchical semi-automated method of segmentation of
greywhite matter of the temporal lobes was undertaken using RESCUE. The
third ventricle was defined posteriorly at the level of the suprapineal recess
and anteriorly at the level of the anterior commissure. Lateral ventricular
volumes included measurement of the temporal horn. Total brain volumes were
measured with the cerebellar tonsils as the inferior marker. The cerebral
hemispheres were separated from the brain-stem at the superior limit of the
pons. All measurements, including assessments of interrater reliability
(A.C.D.J., A.J.), were made blind to diagnosis. The hippocampal and amygdala
measurements were undertaken by one rater (A.C.D.J.).
Reliability studies
Inter-/intrarater reliability studies were undertaken with three raters
(A.C.D.J., S.J., A.J.). Intraclass correlation coefficients (ICCs)
(Bartko, 1966) were 0.95 for
total brain volume, 0.94 for ventricular volume, 0.87 for amygdala volume, and
0.90 for hippocampal volume.
Statistical methods
Categorical variables such as gender were analysed by 2
tests (Table 1). Handedness was
analysed using the KruskalWallis test. The majority of the variables,
in particular the volumes, were analysed by analysis of variance (ANOVA),
where the model concerned involved diagnosis (schizophrenia, normal), gender
(male, female) and their interaction. It was decided to cube-root-transform
the volumes prior to performing the ANOVA. This was done because generally
they showed a strong mean variance relationship (ANOVA assumes equal
variances) and because volume is (distance)3. An initial analysis
of the transformed volume results at the first and second measurement times
strongly suggested that there were no differences between the two diagnosis
groups with regard to the change between the two times but that there were
differences between the averages. To confirm this, the volumes were
re-expressed as difference and mean between and over the two measurement
times. The results of the analyses of differences and means are given in
Table 2. An adjustment for age
differences was made by introducing age difference into the ANOVA as a
covariate for the difference in cube-rooted volumes and mean age for the mean
cube-rooted volumes. For some of the volumes these covariates were
significant, so the results are reported here. The means given in
Table 2 are those for
cube-rooted volumes after adjustment for differences in the covariate
value.
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For bilateral volumes the asymmetry, calculated as:
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RESULTS |
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The normal pattern (Giedd et al, 1996) of right greater than left asymmetry for the temporal lobe and hippocampus was evident, if not significant, for the patients with schizophrenia and the normal controls. No differences in asymmetry between times 1 and 2 were significant. Two mean (over times 1 and 2) asymmetries displayed evidence of a difference between diagnostic groups, these being temporal horn and amygdala. The temporal horn showed a left greater than right asymmetry for patients with schizophrenia but a right greater than left asymmetry for the normal controls. For the amygdala the patients with schizophrenia showed a right greater than left asymmetry, whereas the normal controls showed a left greater than right asymmetry.
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DISCUSSION |
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Temporal lobe
There were no differences between groups in temporal lobe volumes, or
temporal lobe grey or white matter volumes, or over time. Several longitudinal
studies of first-episode adult patients have failed to find progressive
temporal lobe volume changes (De Lisi et al,
1995,
1997;
Gur et al, 1998),
although there are reports of loss of left superior temporal gyral volumes
(Hirayasu et al,
1999) and loss of grey matter
(Mathalon et al,
2001) over periods of 1 to 4 years. The findings contrast with the
reported loss of 7% of temporal grey matter
(Rapoport et al,
1999) in adolescents with childhood-onset schizophrenia over a
4-year period, and a recent study of 100 non-chronic patients where the loss
of temporal lobe grey matter was 7% for men and 8.5% for women
(Gur et al, 2000).
The findings of a left amygdala volume reduction of 15% (95% CI 4-25) is
slightly larger than the 9% (95% CI 6-13) in meta-analytical studies
(Wright et al, 2000)
and greater than any other temporal lobe volume reduction. A time-yoked study
of 42 adolescents with childhood-onset schizophrenia and 74 matched controls
over three time periods showed relative stability of the amygdala and a
non-linear reduction in hippocampal volumes
(Giedd et al, 1999).
Although not all studies have reported hippocampal reductions, recent
meta-analyses (Nelson et al,
1998) indicate bilateral reductions (effect size: 0.37 left, 0.39
right). There was a trend towards a reduction in left hippocampal volume at
time 2 (F=3.4, P=0.07), which is in line with the findings
of loss of hippocampal volume during adolescence after onset of the illness
(Matsumoto et al,
2001).
Gender dimorphism
Male subjects with schizophrenia have larger lateral ventricles. Despite
others' findings of gender dimorphism in the amygdala changing with age
(Goldstein et al,
1999; Gur et al,
2000), here there were no gender by diagnosis interactions. Female
subjects with schizophrenia consistently had the smallest amygdala. Bryant
et al (1999) argue
that temporal lobe structures are gender dimorphic, with male subjects with
schizophrenia having smaller temporal lobe volumes. A meta-analysis
(Wright et al, 2000)
found little supporting evidence for a gender effect. All the structures
examined were larger in males, with a gender by diagnosis interaction only for
the right hippocampus.
Asymmetry
In this study the pathology in adolescent-onset schizophrenia appears to be
predominantly left-sided with left temporal horn enlargement, together with a
reduced left amygdala volume. The left-lateralised changes have been noted
previously (Crow et al,
1989; Bogerts et al,
1990) and have been hypothesised to be of aetiological
significance to the aberrant neurodevelopment of schizophrenia
(Crow, 1997), particularly in
view of the lateralisation to the left temporal lobe of certain language
functions.
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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 August 20, 2001. Revision received November 27, 2001. Accepted for publication December 3, 2001.
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