University Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh, UK
Correspondence: Dr Stephen M. Lawrie, University Department of Psychiatry, Morningside Park, Edinburgh EH10 5HF, UK. Tel: 0131 537 6671; fax: 0131 537 6531; e-mail: s.lawrie{at}ed.ac.uk
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ABSTRACT |
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Aims To determine if temporal lobe volumes reduce during the development of symptoms of schizophrenia in initially well people at high risk of this disorder.
Method A group of 66 people who had at least two first- or second-degree relatives with schizophrenia and a control group of 20 healthy people had a structural MRI scan of the whole brain which was repeated after approximately 2 years. Regions of interest, specifically the amygdalahippocampus complex and the temporal lobes, were traced semi-automatically by three masked raters with good inter-and intrarater reliability.
Results Regional brain volume changes over 2 years did not differ between high-risk and healthy participants. Within the high-risk group, the 19 people with psychotic symptoms (12 at first assessment) had a mean reduction of 2163 mm3 in the right temporal lobe compared with 97 mm3 in the 47 without symptoms (P=0.02).
Conclusions Our findings suggest that people at high risk of schizophrenia with psychotic symptoms show reductions in temporal lobe volumes.
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INTRODUCTION |
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METHOD |
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Participants
Details of the recruitment process have been described in previous papers
(Hodges et al, 1999;
Johnstone et al,
2000). Briefly, individuals with schizophrenia, with a family
history of schizophrenia and with adolescent relatives, were identified from
psychiatric hospital case records in most areas of Scotland. Case-note
diagnoses of schizophrenia were verified with the Operational Criteria
Checklist (McGuffin et al,
1991). We then approached their relatives, and high-risk subjects
aged 16-25 who agreed to participate were given a detailed clinical,
neuropsychological and brain imaging assessment. The clinical assessment
included the Present State Examination (PSE, ninth edition), a structured
psychiatric interview schedule which has been widely used in studies of
schizophrenia (Wing et al,
1974). All these assessments were repeated after approximately 2
years in consenting participants who had enrolled in the first 2 years of the
study.
A control group of healthy individuals without any family history of schizophrenia was recruited from the same areas of Scotland as the high-risk participants. These people were of similar age to the high-risk group and their numbers were comparable to the number of people expected to develop psychosis. Members of the control group were fully examined as above and consenting individuals reassessed after approximately 2 years.
Symptom measures
At each clinical assessment, psychotic and other symptoms were identified
and measured on a videotaped PSE. Participants were initially divided into
five groups on the basis of symptom severity
(Johnstone et al,
2000):
For statistical analysis groups rated 0/1 and 2/3 were collapsed (absence or presence of psychotic symptoms), and those who developed schizophrenia before the second scan could not be included as they only had one scan. It should be noted that some of the high-risk participants had partially or fully rated psychotic symptoms at intake (n=12), but most were working or studying productively and none had schizophrenia or any other psychotic disorder. By 1999, a relatively small number of the whole cohort (n=7) had gone on to meet diagnostic criteria for schizophrenia and we are thus not yet able to examine the predictors and associations of psychosis per se. We should also stress that the current analyses were pre-planned, as were similar analyses of the neuro-psychological data (Cosway et al, 2000), as part of the first phase of the study (Miller et al, 2002).
Brain scanning
Details of the image acquisition and processing are given elsewhere
(Whalley et al,
1999). Briefly, participants underwent MRI scanning on a 1T
Magnetom scanner (Siemens, Erlangen, Germany). Midline sagittal localisation
was followed by a double spin echo sequence to identify any gross brain
lesions and a fast gradient echo sequence for volumetric analysis. The latter
consisted of a 180° inversion pulse followed by a FLASH (fast low angle
shot) collection (flip angle 12°, repetition/echo/inversion times=10/4/200
ms, relaxation delay time 500 ms, field-of-view 250 mm). This gave 128
contiguous 1.88 mm thick slices in the coronal plane. Semi-automated quality
control checks of the signal-to-noise ratio and radio frequency field
homogeneity were made daily. Inhomogeneity in the head coil was corrected for
by scanning a flood phantom after each scan and normalising the data to this.
Repeat scans were conducted on the same scanner, with exactly the same imaging
protocol, after approximately 2 years. The scanner was not modified during the
study.
Images were processed on Sun Micro-systems workstations using the software package Analyze (version 7.5, Mayo Foundation, Rochester, Minnesota, USA). Seeds were placed in regions of interest, thresholds adjusted by eye and limits placed manually to separate adjoining structures. The temporal lobes and amygdalahippocampus complex volumes were defined according to the criteria of Suddath et al (1990) and Shenton et al (1992). The temporal lobe measurements started at the temporal pole, the amygdalahippocampus complex volume measurements were commenced when the temporal stem white matter was first observable, and the posterior boundary for both was taken as the first slice in which the crus fornicis fibres formed the medial wall of the lateral ventricle. The posterior boundary of the prefrontal lobes was taken as the first slice of the corpus callosum. Other structures were outlined by standard criteria or naturalistic boundaries as in our previous studies (Lawrie et al, 1999, 2001; Whalley et al, 1999) for exploratory analyses.
Volumetric image processing was performed by three raters (H.C.W., S.S.A., J.N.K.) with good interrater reliability: mean intraclass correlation coefficient 0.92, range 0.78-0.99. The main rater (H.C.W.) also measured her intrarater reliability every 6 months (mean intraclass correlation coefficient 0.94, range 0.80-1.00). Measurement error was quantified by dividing the mean difference between a pair of ratings by the mean volume of the two. Expressed as a percentage, the mean error over time was less than 1% for the whole brain and temporal lobes, 3.2% for the amygdalahippocampus and 1.7-5.5% for the remaining structures other than the third ventricle (Whalley et al 1999). The scans were identified by code number and date of birth only, so that the raters were masked to group membership.
Statistical analysis
All statistical testing was conducted using the Statistical Package for the
Social Sciences (SPSS version 10.0 for PC). Demographics were compared between
groups with analysis of variance and the chisquared test. In the high-risk
group, symptom ratings on the PSE were scored as the highest symptom levels
over the first 5 years of the study, dichotomised into groups of 0/1 (no
psychotic symptoms ever) and 2/3 (psychotic symptoms). Any differential change
over time in the high-risk and healthy control groups was examined with
repeated measures analysis of variance (ANOVA), looking for group x time
interactions. The same test was employed to compare change in high-risk
individuals with and without symptoms. The mean absolute change in regional
volumes was calculated as the mean difference between the two scans (scan
2scan 1), such that a negative value indicates volume reduction.
Relative change as a percentage was calculated with reference to the
appropriate volume on the first scan, i.e. ([scan 2scan 1]/scan 1)
x 100.
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RESULTS |
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Changes in regional brain volumes by symptoms
Nineteen of the high-risk participants had psychotic symptoms (12 at
baseline) and 47 did not. The demographic characteristics of these two groups
are given in Table 3. Women and
shorter individuals were non-significantly overrepresented in the high-risk
group with symptoms. There was little difference in the time between scans in
the two groups: 1.7 (s.d.=0.2) years and 1.8 (s.d.=0.5) years,
respectively.
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Repeated measures ANOVA found one significant group x time interaction, in the right temporal lobe (F1,64=5.4, P=0.023). There was no significant interaction in the left (F1,64=0.2, P=0.7) or right (F1,64=0.7, P=0.4) amygdalahippocampus, or in the left temporal lobe (F1,64=1.0, P=0.3). Table 4 lists the absolute and relative changes in regional volumes in the two groups. The mean absolute reduction in the right temporal lobe in high-risk individuals with symptoms was 2163 mm3 compared with a reduction of 97 mm3 in those without symptoms. These represent relative reductions of 2.5% and 0.04%, respectively (Fig. 1). There are similar reductions in volume in the left temporal lobe (2.3% and 0.8%, respectively). The differences in absolute and relative changes are similar or greater in other structures such as the left and right prefrontal lobes, but the measurement error and variance are also higher.
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A post hoc repeated measures ANOVA of a group x time x gender interaction for the right temporal lobe volumes in high-risk participants was not significant (P=0.5). Neither of the high-risk groups significantly differed from the control group in the changes in right temporal lobe volume. The high-risk participants with psychotic symptoms at baseline and those who developed psychotic symptoms subsequently also did not differ significantly on this measure. As the numbers in the three main subject groups were unequal, we conducted paired t-tests for within-group changes in temporal lobe volumes: both left and right sides showed statistically significant reductions in those with symptoms (both P<0.015) but not in those without (both P>0.25), and the brains of control subjects showed significant reductions only on the left side.
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DISCUSSION |
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Methodological considerations
This novel finding is unlikely to be artefactual. We tested two specific
hypotheses although we did so for bilateral structures in two
different contrasts, these were not independent and would not, therefore, be
suitable for a Bonferroni correction. The volume calculations were done by
masked raters with good inter- and intrarater reliabilities, and measurement
error was less than the main difference we found. High-risk participants with
and without symptoms did not substantially differ in descriptive variables;
the greatest difference was in gender distribution, but we found no symptom
x time x gender interaction.
The results do, however, need cautious interpretation. We analysed the data by symptoms rather than psychosis both to optimise statistical power and because the causes of symptom development in schizophrenia are so poorly understood. It is not therefore possible to state whether these results apply to those who will develop psychosis rather than individual psychotic symptoms, although the symptomatic participants had at least partial or isolated delusions or hallucinations and the diagnosis of schizophrenia is largely made on the grounds of these symptoms. We do not expect all the high-risk group with individual psychotic symptoms to develop frank schizophrenia, and symptoms fluctuate over time for unknown reasons. We are also not able to state whether the changes in brain structure precede or follow symptoms, as many of the symptomatic high-risk individuals had symptoms at baseline assessment. It is unlikely that the symptoms themselves effect volume reductions, but even if the temporal lobe reductions are primary, an explanation is required.
The measurement error of the volumetric technique we used is more likely to have obscured differences where they actually existed rather than to lead to false positive results. This is a possible explanation for our failure to find volume reductions in the amygdalahippocampus in high-risk participants, particularly those with psychotic symptoms. Measurement error is in the region of 5% for these and other relatively small structures. Our previous findings of reduced amygdalahippocampus volumes at baseline could imply that those with the smallest volumes would be most likely to develop symptoms, but this is not the case at least thus far (Lawrie et al, 2001). Alternatively, the reduced volumes of the amygdalahippocampus complex usually found in schizophrenia may only be manifested with the onset of psychosis per se.
Imaging brain development
The imaging literature on development changes in brain structure is
relatively sparse. Most brain development is completed in the first few
postnatal months, but competitive elimination of synapses, axonal myelination
and dendritic arborisation continue throughout life
(Huttenlocher, 1990;
Bourgeois & Goldman-Rakic,
1994; Jernigan & Sowell,
1997). Some MRI studies have found age-related reductions in
T2-weighted signal suggestive of myelinatioin throughout
the hemispheres in adolescence and early adulthood
(Jernigan & Sowell, 1997).
We are aware of only three MRI studies employing similar measures of regional
brain volumes in control groups of similar age to our own, two from the same
research group in an overlapping sample, which suggest that the frontal and
temporal lobes reduce in size during early adulthood
(Jernigan & Sowell, 1997;
Bartzokis et al,
2001), possibly due to synaptic pruning. Automated
voxel-based morphometry studies support these findings, but suggest the
reductions are greater in the frontal lobes
(Giedd et al, 1999;
Sowell et al, 1999).
Our results in healthy control participants are compatible with these
findings, particularly if measurement error is taken into account. This could
also explain the apparent reductions over time of ventricular volumes in the
control group, but it is uncertain whether ventricular volumes begin to
increase from the age of 20 years
(Jernigan et al,
1991) or 30 years (Pfefferbaum
et al, 1994) in healthy individuals.
These processes do not appear from our current data to differ significantly in all the high-risk participants, or in either of the high-risk groups, compared with the healthy control group. We cannot, therefore, determine whether the reductions in the temporal lobes in symptomatic high-risk individuals are attributable to physiological or pathological processes. The patterns of change in the temporal lobes are similar in the symptomatic high-risk and control groups, suggesting that the development of symptoms may be triggered by physiological events in the otherwise predisposed (Feinberg, 1982; Weinberger, 1987). It should be noted, however, that whole-brain volume and prefrontal lobe reductions are only apparent in the high-risk group with symptoms, which suggests that synaptic pruning may be more widespread in these people but greatest in the temporal lobes. It should also be noted that post-mortem studies do not always find reductions of the amygdalahippocampus and prefrontal lobes in schizophrenia (Harrison, 1999).
Clinical implications
Structural MRI studies have reported that abnormalities of the hemispheres
(DeLisi et al, 1997)
and temporal lobes (Rapoport et
al, 1999) may progress in the first few years after the onset
of schizophrenia in patients of similar ages to our study group and at a
similar rate (about 1% per year). Other studies have, however, localised
changes to the frontal lobes (Gur et
al, 1998) or found them to be limited to the lateral
ventricles in poor-outcome subgroups
(Lieberman et al,
2001). These changes could be due to antipsychotic medication
effects, but none of the high-risk participants reported here was taking such
medication when assessed or, indeed, at any previous time. The differences
between reports may reflect differential measurement errors in semi-automated
studies, and we are currently engaged in an entirely automated comparison. As
far as psychotic symptoms can be localised, temporal lobe abnormalities have
been linked to auditory hallucinations similar to those described by our
high-risk participants (Shenton et
al, 1992; Lawrie &
Abukmeil, 1998). We cannot tell from the present analysis whether
particular parts of temporal lobes are reducing or whether reductions
represent a general loss of temporal lobe tissue, but we are currently using
more detailed techniques to determine this and any specific relationships with
particular psychotic symptoms. These novel analytical methods may be
sufficiently sensitive for clinical use.
Our scanning results are compatible with our neuropsychological findings, in the same study group, of a decline in memory (and executive) function as psychotic symptoms develop (Cosway et al, 2000). It may be that the development of psychotic symptoms is triggered by one or more processes associated with reduction in temporal lobe volume and that the processes lead to the development of a psychotic illness and continuing reduction in temporal lobe volumes in at least some people. These findings therefore raise the possibility that people destined to develop schizophrenia might be identifiable before (or at least while) the disorder develops, and might potentially benefit from treatment with antipsychotic or even neuroprotective drugs.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication September 3, 2001. Revision received April 4, 2002. Accepted for publication April 9, 2002.
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