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Grey matter changes over time in high risk subjects developing schizophrenia
www.elsevier.com/locate/ynimg NeuroImage 25 (2005) 1023 – 1030
Grey matter changes over time in high risk subjects developing schizophrenia Dominic E. Job,T Heather C. Whalley, Eve C. Johnstone, and Stephen M. Lawrie Division of Psychiatry, University of Edinburgh, The Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, Scotland, UK Received 31 March 2004; revised 21 December 2004; accepted 6 January 2005 Available online 3 March 2005 Schizophrenia affects approximately 1% of the population and is associated with reductions in brain volume, but when these are first evident is unknown. Magnetic resonance imaging (MRI) has demonstrated abnormalities of brain structure, particularly of the temporal lobes, in schizophrenia. A study of brain structure in individuals destined to develop schizophrenia, before they do so, is crucial to understanding the illness. We used Voxel Based Morphometry (VBM) to map changes in Grey Matter Density (GMD) in 65 young adults at high risk of schizophrenia, for familial reasons, and 19 healthy young adults, over a period of approximately 2 years. All subjects were antipsychotic naive at both scans. No increases in GMD were found in any of the groups. Within the high-risk group significant declines in GMD were found in the temporal lobes, the right frontal lobe and right parietal lobe. In the control group a decline was found in the right gyrus rectus. No significant differences over time were found between any of the groups. Those individuals at high risk who had transient or isolated psychotic symptoms showed a different spatial pattern of reductions in GMD than those who did not in within group comparisons. In addition, those individuals at high risk who later developed schizophrenia also showed a different spatial pattern of reductions in GMD in the left temporal lobe and right cerebellum, from 2 to 3 years before they were diagnosed. These particular reductions may therefore be able to predict the later onset of schizophrenia. D 2005 Elsevier Inc. All rights reserved. Keywords: Schizophrenia; Grey matter; Brain
Introduction The Edinburgh High Risk Study (EHRS) is the first to prospectively examine the changes in brain structure of people at high risk of schizophrenia for familial reasons, before any individuals fall ill (Johnstone et al., 2000). We compared the changes over time in high risk subjects who had two scans about 2 years apart, in the three groups: well controls (n = 19), high-risk
T Corresponding author. Fax: +44 131 537 6531. E-mail address: [email protected] (D.E. Job). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2005.01.006
subjects without any psychotic symptoms (n = 47), and high-risk subjects with transient or isolated psychotic symptoms (n = 18). Eight of the people from the transient or isolated psychotic symptoms group have subsequently developed schizophrenia, on average 2.34 years after their first scan. Previous cross-sectional imaging studies in schizophrenia found reduced GMD compared to controls, particularly in the temporal lobes, in people with established disease and in the first-episode of illness (Lawrie and Abukmeil, 1998; Lawrie et al., 1999; Shenton et al., 1992; Suddath et al., 1990; Wright et al., 2000). These studies show that structural brain changes are present around the time of onset of psychosis, but the chronology is unknown. However, post-mortem schizophrenia studies have shown mixed findings; some report no change or an increase in GMD in the ventral striatum (Lauer et al., 2001), no change specifically in the amygdala (Chance et al., 2002), whilst others find decreases in GMD (McDonald et al., 2000) in the left parahippocampal gyrus and left fusiform gyrus, similar to those found in MRI studies. The schizophrenic subjects in these post-mortem studies differ greatly from most patients and particularly our high-risk group in age, illness and medication duration, (family history), and are therefore not directly comparable. Further to this, there are differences in the analysis methods used by each approach. Post-mortem studies have to account for individual and regional tissue shrinkage, differences in time to fixation and the fixation period itself, and they measure volume, not maximal points of change, as in VBM. Structural MRI of the brain at first scan in the subjects in this sample revealed that there was lower GMD in the amygdala– hippocampal complex (AHC) in people at high risk, but even less in first-episode patients, compared to healthy controls (Job et al., 2002, 2003; Lawrie et al., 1999, 2001). A subgroup of those highrisk subjects and controls were scanned on a second occasion approximately 2 years later. Some of the high-risk participants had experienced transient or isolated psychotic symptoms during this time. Subsequently, 8 of the high-risk participants went on to develop schizophrenia (Johnstone et al., 2000). We therefore tested a three-part hypothesis in this report. Firstly, we determined whether or not people at high risk of schizophrenia, as a group, show reductions in GMD in the temporal lobes and AHC over time, compared with a control group, that might indicate a general
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and probably genetic effect. Secondly, we examined whether these structures showed greater reductions in GMD in high-risk participants with transient or isolated psychotic symptoms, than in those without any psychotic symptoms. Thirdly, we examined changes over time in the 8 high-risk participants who have since developed schizophrenia, for reductions that are evident preceding illness onset.
Methods Subjects The subjects were recruited for the EHRS (Hodges et al., 1999; Johnstone et al., 2000). A total of 162 high risk subjects who had at least two first or second degree relatives with schizophrenia, were recruited over a period of 4 years. Of this group, 66 people and 19 healthy controls, matched group wise for age, had a structural MRI scan of the whole brain which was repeated after approximately 2 years in the first 5 years of the study. Others were either recruited too late or became ill too soon for two scans to be conducted in this phase. One of the high-risk subject’s scans was lost in a computer malfunction (n = 65). Voxel Based Morphometry (VBM) (Ashburner and Friston, 2000; Wright et al., 1995) was used to compare the groups and changes within groups, specifically examining the amygdala–hippocampal complex and the temporal lobes. This is the first application of VBM to our longitudinal data. Control subjects had been recruited from local youth groups and the social networks of the high risk subjects on the basis that they had no major psychiatric disorders or family history of the same. Details of the two subject groups are presented in Table 1. Ethical approval was obtained from the Psychiatry and Psychology subcommittee of the Lothian Region Ethics Committee and all subjects gave written informed consent. The eight high-risk subjects who developed schizophrenia did so on average 2.34 years (SD 1.02) after their first scans and 0.81 years (SD 0.76) after their second scans. The rationale of the Edinburgh High-Risk Study rests on two pillars (Johnstone et al., 2000). The first is that the risk of schizophrenia in subjects with a family history of the disorder, such as these people have, is at least 10 times that in the general population. The second is that schizophrenia is a disorder with a restricted age of onset particularly so in men. Therefore, for men, if they have not developed the psychosis by the age of 30, the probability is that they will never do so. In women, onsets can be later but by 31st July 2004, the closure date of this second 5-year Table 1 Demographic characteristics of high-risk and control study participants
Age, years (SD)a Male, Female Handedness: Mixed, Left, Right Height (SD) Paternal social class at birth: manual, non-manual, unknownb a
High risk (n = 65)
Control (n = 19)
21.4 (2.7) 34, 31 2, 6, 57
21.0 (2.1) 12, 7 2, 2, 15
172.2 (10.7) 30, 33, 2
173.2 (10.8) 13, 6, 0
Mean age at first assessment. According to the Occupational Classification of the Registrar General [HMSO, 1991].
b
study when the majority of the subjects will be near the age of 30, almost all of those destined to develop schizophrenia will have done so. The age of onset of schizophrenia differs between genders by 3 to 4 years, but it has been reported that this difference is not evident in familial cases, reviewed in Gattaz and Ha¨fner (1999), who conclude that in familial cases such as ours, this differential in age of onset is not apparent. There is, however, no means of establishing who those few who may yet become ill over the next few years may be and no instrument can tell us this. Mental states of the subjects have been assessed every time a scan is conducted (Johnstone et al., 2000). In this study, the high-risk subjects have been divided into those who have never shown possible or definite psychotic symptoms, those who have shown transient or partial psychotic symptoms on at least one occasion but had not developed schizophrenia by 2003 and those who by 2003 had developed schizophrenia. The criteria for these categories are described in Johnstone et al. (2000). Transient psychotic symptoms are symptoms, usually delusions and or hallucinations, which occurred briefly, for minutes or at most a few hours, and which in the case of delusions were not thereafter believed by the subjects or in the case of hallucinations occurred during this brief period and not again. Isolated hallucinations are those which occurred sometimes several times which were brief, for example, a name being called or a phrase repeated but which were not associated with any other misperceptions, delusions or other possibly psychotic psychopathology. Forty percent of both the control and high-risk subjects stated that they had used cannabis at some time and a small number of both groups also used other recreational drugs occasionally. No exclusions were made on the grounds of substance use from either the control group or the high-risk group. Image processing MR brain scanning was performed on a 42 SPE Siemens (Erlangen, Germany) Magnetom operating at 1.0 T. Midline sagittal localisation was followed by two sequences to image the whole brain. The first scan was a double spin echo sequence which gave simultaneous proton density and T2-weighted images (TR = 3565 ms, TE = 20 ms and 90 ms, 31 contiguous 5 mm slices in the Talairach plane, field of view 250 mm 250 mm) to identify any gross brain lesions. The second scan was a three-dimensional Magnetisation Prepared Rapid Acquisition Gradient Echo (MPRAGE) sequence consisting of a 1808 inversion pulse followed by a Fast Low Angle Shot (FLASH) collection (flip angle 128, TR = 10 ms, TE = 4 ms, TI = 200 ms and relaxation delay time 500 ms, field of view 250 mm 250 mm) to give 128 contiguous dslicesT of 1.88 mm thickness. Immediately after each subject’s scan, a large plain test object filled with light oil was scanned in exactly the same place in the coil and in the same orientation as the subject’s head. The test object data was used to correct for inhomogeneity in the radiofrequency coil. Inhomogeneity correction standardises each image to account for scanner inhomogeneity and potential changes in the scanner over time. Repeat scans were conducted on the same scanner, with exactly the same imaging protocol, after approximately 2 years. Our Voxel-Based Morphometry was performed using the SPM99 toolbox (http://www.fil.ion.ucl.ac.uk/spm/spm99.html). A study-specific template and a priori probability maps for grey matter, white matter and cerebral spinal fluid were constructed. Using these study specific templates all of the images in the control
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and high-risk group were spatially normalised and segmented, eliminating large-scale differences between the subjects, using a 12-point linear affine transformation only. All of the resulting GMD segments were then smoothed at 12 mm full width at half maximum (FWHM) before being entered into our statistical analysis. It should be noted that GMD refers to the probability of finding grey matter (GM) in a unit volume, not to cell packing or absolute volume. The VBM protocol used in this analysis cannot give an accurate quantification of actual volume reduction. Statistical analysis Group comparisons were performed using a random effects analysis. A repeated measures time groups interaction (ANOVA) statistical model in SPM99 based on the general linear model, was used to replicate the volumetric analysis performed in our previous region of interest (ROI) study (Lawrie et al., 1999, 2001, 2002; Whalley et al., 1999). However, a groups time interaction is not the most useful test for clinical purposes to examine the changes within the high-risk group. In the case of the ANOVA, changes in the control group, significant or not significant, dilute the measurements in the high-risk group, thereby smoothing the measurements and producing a less sensitive test. An alternative method that allows for the differences in spatial patterns of significant changes in the control group and high-risk sub-groups to be taken into account, but not directly compared, in within group comparisons is a masking method not available in our previous volumetric ROI study. This alternative method uses masking to exclude any change over time in the control group (paired F test, P-uncorrected = 0.05), at voxel level, from the changes in the high-risk group ( Pcorrected = 0.05). With this conservative method of masking, groups are not directly compared, but any significant area of change in the second group, the control group in this example, is excluded leaving only changes exclusive to the primary group in the statistical assessment. This statistical technique has previously been used in several functional imaging studies (Cabeza et al., 2004; Critchley et al., 2000; Davis and Johnsrude, 2003; Farrer et al., 2003; Morcom et al., 2003). It can been seen, for example, in Table 2 and Fig. 1, that the left uncus, Brodmann area 20, finding is shown in the masked and unmasked results. The coordinates of these two points differ by less than 2 mm. This shows that the maximal point of change in the uncus in the unmasked contrast has been excluded in the masked contrast, but due to spatially more extensive reductions in those high risk subjects with symptoms, this region is still significantly reduced in the masked within group contrast, and therefore could be useful in a diagnostic test. As the masked paired t test does not include the non-significant changes in the control group, this test cannot be used to conclude that there are greater differences in the high risk group than in the control group, as the null hypothesis of no group differences still cannot be rejected for the control group in the area outside the mask. Since volumetric differences in the AHC and temporal lobes are the most consistent findings in the high risk and schizophrenia literature (Job et al., 2002; Lawrie and Abukmeil, 1998; Lawrie et al., 2001; Shenton et al., 1992; Suddath et al., 1990; Velakoulis et al., 1999; Wright et al., 2000), we further restricted the analyses to voxels within these regions (Small Volume Correction, SVC). These a priori SVCs match the AHC and temporal lobe regions examined in our previous volumetric ROI study. These SVCs (bilateral) were created by manually editing the non-smoothed EHRS T1 template to define the small volume. In order to strengthen
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Table 2 GMD reductions over time in high risk subjects with transient or isolated psychotic symptoms (n = 18, paired t test) Voxel P (corrected)
Talairach coordinates x, y, z (mm)
0.044
37.6,
40.6,
34.1
0.006 0.008 0.033
47.5, 45.5, 46.5,
32.1, 28.1, 12.4,
20.3 1.4 33.9
0.046 0.020 0.050
35.6, 24.8, 21.8,
11.4, 9.2, 14.0,
33.1 29.0 27.1
0.030
26.7,
4.8,
18.3
Points of maximal change with no masking Right Cerebellum, Posterior Lobe, Cerebellar Tonsila Left Fusiform Gyrus, BA 20b Left Superior Temporal Gyrusb Left Inferior Temporal Gyrus, BA 20b Left Uncus, BA 20b Left Uncusc Left Parahippocampal Gyrus, BA 28c Right Parahippocampal Gyrus, Amygdalac
Points of maximal change with masking This mask excludes any areas of significant change in those high risk subjects who do not have any psychotic symptoms (mask: n = 47, F test at P = 0.05 uncorrected threshold) 0.018 36.2, 28.9, 4.3 Left superior lateral surface of hippocampusa 0.000 49.5, 26.5, 25.6 Left fusiform gyrus, BA 20b 0.024 27.7, 9.4, 32.3 Left uncusb 0.029 33.7, 10.4, 34.0 Left uncus, BA 20b 0.037 39.6, 12.5, 36.4 Left inferior temporal gyrus BA 20b 0.050 49.5, 30.9, 3.4 Left superior temporal gyrusb NB BA: Brodmann area. a Corrected at whole brain level. b Temporal lobe small volume correction. c Amygdala hippocampal complex small volume correction.
the validity of our temporal lobes and AHC SVCs, we also applied two SVCs to the occipital lobes, where no changes were expected and none were found. The first occipital lobe SVC closely matched the correction for multiple comparisons of the temporal lobe SVC, and the second closely matched the AHC SVC. Notes concerning the figures In some of the figures, GM reduction appears to be outside of the brain. This is due to averaging and smoothing of the processed images, and the fact that thresholds used for the figures are different from those used in the statistical analysis so that the areas of reduction are clearly visible. No tissue outside the brain should enter into the SPM analysis as all of the images are masked and cleaned to remove non-brain tissue. None of these extra cerebral areas reach statistical significance.
Results In our first comparison, we constructed statistical maps of changes over time in the high-risk and control groups. Using the same statistical analysis (a repeated measures ANOVA, for group time interactions) as used in our previous ROI study, there were no significant differences in GMD changes, over 2 years, between the control and the high-risk group, in keeping with our previous ROI study (Lawrie et al., 2002). However, when we examine the changes over time in the high risk group alone, and then the control
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Fig. 1. GMD reductions over time in those at high risk of schizophrenia who had transient or isolated psychotic symptoms. Green crosshairs indicate reductions in GMD exclusive to those high-risk subjects with symptoms (excluding changes in those high-risk subjects without any psychotic symptoms). Blue crosshairs indicate reductions in those at high risk of schizophrenia with transient or isolated psychotic symptoms that were excluded by the mask. The blue and green crosshairs show the P-corrected maximum points of change as reported in Table 2. (Colour blobs are thresholded at P-uncorrected = 0.005).
group alone, it is evident in the more sensitive VBM analysis that there are many significant changes in the high risk group (n = 65), and high risk sub groups (n = 47, 18 and 8), and only one significant change in the control group (n = 19). These findings were further examined using the within group masking method for their clinical diagnostic potential. Using masking at voxel level, a more spatially specific statistical method not available in our ROI study, previously unreported reductions in GMD over time are seen. We created a mask of any change over time in the control group (paired F test, P-uncorrected threshold = 0.05), at voxel level, and used this voxel mask to remove any significant control group changes from the reductions in the high-risk group (paired t test, P-corrected threshold = 0.05. See the supporting table and supporting figure). It is important to note that the masking contrasts do not examine differences between groups because in this case no information from the control group (the group used to define the mask here) is included in this contrast. The remaining reductions in the masked high-risk group were in the left and right fusiform gyrus, left cingulate gyrus, right inferior parietal lobule, left uncus, left and right middle temporal gyrus, left and right inferior temporal gyrus, right superior temporal gyrus, the left and right parahippocampal gyrus and the lateral border of the left amygdala. However, this voxel masking method has the problem that significant changes in the high-risk group can be excluded completely by this means. The changes over time in the highrisk group without the use of masking are therefore also given to facilitate comparison with our previous ROI volumetric study (Lawrie et al., 2002). Without the exclusion of the significant control group changes, reductions in GMD in the high-risk group
are seen in the right cingulate gyrus, left and right cerebellum, the right occipital lobe, right uncus and left superior temporal gyrus. Exclusive masking can also affect the volume to surface area ratio of a volume and therefore alter the correction for multiple comparisons; hence, there are three exclusive points of GMD reduction in Table 3, but only one non-exclusive point. The two additional points seen in the masked contrast did not reach significance in the unmasked contrast, but due to the reduced volume of the masked contrast there were fewer multiple
Table 3 GMD reductions over time in high risk subjects who have developed schizophrenia (n = 8, paired t test) Voxel P (corrected) 0.05
Talairach coordinates x, y, z (mm) 24.8,
10.2,
29.0
Points of maximal change with no masking Left uncus, Brodmann Area 28a
Points of maximal change with masking This mask excludes any areas of significant change in those people at high risk who have transient or isolated psychotic symptoms, but have not developed schizophrenia (mask: n = 10, F test at P = 0.005 uncorrected) 0.044 40.6, 44.6, 38.1 Right cerebellumb 0.043 51.1, 16.1, 31.2 Left inferior temporal gyrus, Brodmann area 20c 0.05 24.6, 10.2, 28.9 Left uncus, Brodmann area 28a a b c
Amygdala hippocampal complex small volume correction. Corrected at whole brain level. Temporal lobe small volume correction.
D.E. Job et al. / NeuroImage 25 (2005) 1023–1030
comparisons and therefore a slightly less strict correction was applied. In our second comparison of the high-risk subjects with transient or isolated psychotic symptoms (n = 18, paired t test, P-corrected threshold = 0.05. Table 2, Fig. 1), we found reductions over time in the right cerebellum, left fusiform gyrus, left uncus, left superior temporal gyrus, left inferior temporal gyrus, left and right parahippocampal gyrus and the right amygdala. If we exclude any significant changes in the high-risk group who did not have any psychotic symptoms, using a mask (n = 47, paired F test, P-uncorrected threshold = 0.05), from the reductions in those who do have transient or isolated psychotic symptoms, we still see reductions in the left fusiform gyrus, left uncus, the left superior and inferior temporal gyri and the left superior lateral surface of the hippocampus. Our previous ROI study found a significant reduction in the right temporal lobe between the high-risk group with transient or isolated psychotic symptoms and those high-risk subjects without any psychotic symptoms (ANOVA), but we found no difference between these groups in this VBM study (ANOVA). Those high-risk subjects with transient or isolated psychotic symptoms did not have severe enough symptoms to warrant them being diagnosed as having a formal psychiatric illness, or to notably impair their everyday functioning. In our third comparison of those high risk subjects that have developed schizophrenia at their second scan (n = 3, of whom 1 is male) or since their second scan (n = 5, of whom 3 are male) (total n = 8, paired t test, P-corrected threshold = 0.05. Table 3, Fig. 2), excluding any significant changes seen in those high-risk subjects who had transient or isolated psychotic symptoms but did not develop schizophrenia (mask: n = 10, paired F test, P-uncorrected threshold = 0.05), we see reductions in GMD in the left inferior temporal gyrus, left uncus and the right cerebellum. In the control group alone, one reduction in GMD was found in the right gyrus rectus at 0.004 P-corrected (n = 19, paired t test, P-corrected threshold = 0.05. Talairach coordinates: x = 4.0, y = 20.8, z = 24.8, Fig. 3). There were no increases in GMD over time in any of the groups. The differences in group sizes could potentially confound our results, although it should be noted that we found reductions in the sub-sample of 8 high risk subjects that have developed schizophrenia. A brief review of previous results At baseline those subjects at high-risk (n = 146) were subtly different from controls (n = 36) (Job et al., 2003). Subjects at high-
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Fig. 3. GMD reductions over time in the 19 control subjects. The blue crosshair shows the P-corrected maximum point of change. (Colour blobs are thresholded at P-uncorrected = 0.0005). NB The colour bars in the figures show the Z scores corresponding to colours in the images. The numbers at the bottom left of each brain slice shows the height of the slice on the z axis in MNI coordinates. Crosshairs are accurate to the nearest 2 mm.
risk showed reduced grey matter in left and right anterior cingulate ( P-corrected b 0.05) with a trend to a difference in the left parahippocampal gyrus ( P-corrected b 0.1). The high-risk subjects showed no increases compared to controls. At baseline, those at high risk who did not eventually fall ill (n = 130) were not different to those who fell ill (n = 16), nor were there any associations of transient or isolated psychotic symptoms at that time (n = 101 nonsymptomatic vs. n = 42 with transient or isolated psychotic symptoms; 3 did not have clinical interviews at that time).
Discussion We did not find evidence to support the first part of our hypothesis, namely a reduction in temporal lobe volumes in all high-risk individuals as compared to controls. However, using exclusive masking, a statistical technique used more often in functional MRI (Cabeza et al., 2004; Critchley et al., 2000; Davis and Johnsrude, 2003; Farrer et al., 2003; Morcom et al., 2003), the within group analyses do provide information that may be useful for early diagnostic purposes. This masking technique was not applicable to our previous ROI volumetric data. Our findings do not support the second part of our hypothesis, in that the left and right temporal lobes was reduced in volume in high-risk subjects with transient or isolated psychotic symptoms, compared to those high-risk subjects without psychotic symptoms. Finally, the third part of our hypothesis is supported since the 8 high-risk subjects
Fig. 2. GMD reductions over time in those 8 people in the high-risk group who have since developed schizophrenia. Green crosshairs indicate reductions in GMD in those 8 people who have developed schizophrenia, excluding any change in those 10 high risk subjects who had transient or isolated psychotic symptoms, but did not develop schizophrenia (Colour blobs are thresholded at P-uncorrected = 0.001). The green crosshairs show the P-corrected maximum point of change as reported in Table 3.
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who now have schizophrenia showed GMD reductions in the right cerebellum and left temporal lobe 2 years before developing schizophrenia. In contrast, lower GMD at baseline in the high-risk subjects compared to healthy controls did not predict schizophrenia in the larger number of subjects who were only scanned once. These results suggest that subjects at high risk of schizophrenia for genetic reasons have trait and presumably genetically mediated reductions in cortical volumes in early adulthood as seen in the baseline analysis, and that changes are greater, as seen in the previous ROI study, in those who also have a liability to transient or isolated psychotic symptoms. Most people with this dintermediate phenotypeT will not however develop schizophrenia. This is associated with still further subtle changes. We have analysed the data by transient or isolated psychotic symptoms and by psychosis per se so that these results apply to those who develop schizophrenia and to those with transient or isolated psychotic symptoms, and because the pathophysiology of schizophrenia is poorly understood. The symptomatic subjects had transient partial or isolated delusions and hallucinations, but most were working and not functionally impaired, and none were thought to be ill. The diagnosis of schizophrenia was made when these psychotic symptoms were sufficiently severe or sustained to justify such categorisation in terms of PSE/Catego (Wing et al., 1974) and ICD10 (WHO, 1992) criteria. In the control group alone, a reduction in GMD over time is seen in the right gyrus rectus, bordering the orbital frontal gyrus. We have examined all scans for artefacts, but found none. Sowell et al. (2003) showed that GMD reduces the right gyrus rectus between the ages of 10 and 20 years, 20 and 30 years, and 30 and 40 years, and attributes this loss of GM to a gain in myelination, with an increase in GM between the ages of 60 and 90 years, in normal controls. Giedd et al. (1999) also found a decline in GM in the frontal lobe during post-adolescence (11– 22 years). In contrast, Sowell et al. (2003) found that a decrease in normal temporal lobe GMD occurs later, from an approximate age of 50 years. It may be that we did not find a similar GMD reduction in the gyrus rectus in the high-risk subjects because of greater than normal variability in the high-risk group, but there could be genetic reasons. We found bilateral reductions in the high risk group as a whole, mainly in the temporal lobes, but also in the cingulate and anterior cingulate as well as unilateral reductions in the right frontal lobe, right inferior parietal lobe and right cerebellum. Those high-risk subjects who had experienced transient or isolated psychotic symptoms over the years covered by this report showed reductions mainly in the left temporal lobe, and also the right cerebellum and right amygdala. When excluding any change in those high-risk subjects without any psychotic symptoms from the symptomatic group, we only found changes in the left temporal lobe and right cerebellum. Considering these data from the point of view of clinical prediction, this suggests that those at high risk as a whole suffer bilateral reductions in the temporal lobes, but those at high risk who go on to develop symptoms show more loss in the left temporal lobe and right cerebellum, and in some of them 2 years before the onset of psychosis. The left uncus finding in those 8 high-risk subjects who have developed schizophrenia is marginal since it is only picked up by the AHC SVC. This SVC is derived from the unsmoothed average image, which is intended to encompass the entire AHC and therefore includes some surrounding structures. This finding is evidently part of the edge of a larger area of GMD reduction in the temporal lobe, which is mostly outside the AHC. Findings in this
small group of 8 individuals are limited due to the small number of scans. Nevertheless, differences were found, in keeping with our hypothesis, and have not previously been reported in high-risk subjects or this long before illness onset. Thompson et al. (2001) found that temporal lobe grey matter loss was absent early, but became pervasive later, in early onset schizophrenia (aged 13.9 F 0.8 years at first scan). Left medial temporal lobe loss is also apparent between the prodromal phase, and first episode of psychosis, specifically in subjects who had sought psychiatric attention (Pantelis et al., 2003). Velakoulis et al. (2002) found reduced volume on the left side only, in patients at first presentation with schizophrenia, and that reduced grey matter in the right medial temporal lobe (anterior hippocampus, uncus, parahippocampal gyrus), medial cerebellar and bilateral anterior cingulate, developed in relation to the increasing duration of their illness. Our findings in anti-psychotic naive high-risk subjects, taken together with these other relevant findings in medicated prodromal and first presentation subjects (Pantelis et al., 2003; Thompson et al., 2001; Velakoulis et al., 2002), suggest that those at high risk of schizophrenia have reduced grey matter volumes, predominantly bilaterally in the temporal lobes, and that those who go on to develop symptoms have more severe reductions in the left temporal lobe 2 years before the onset of psychosis, a loss which could continue until the onset of psychosis. Subjects may then suffer further reductions in the right temporal lobes following their first onset. These lateralised findings have precedence (Crow, 2002), but brain torque and other asymmetric structures may account for some of this apparent lateralisation. Automated normalisation methods, such as those currently used in VBM could be negatively affected by brain torque as there may be differences in brain torque between our groups and this could lead to false-positives due to shape differences, not GMD differences. In the 8 psychotic subjects, the left uncus and temporal cortex reduction may relate to impairments in emotional expression recognition, which in turn may foster anxiety and paranoia (Dilger et al., 2003; Gray and McNaughton, 2000). It is therefore of interest that psychopathological assessments in the high-risk sample as a whole have shown that anxiety, years before psychotic symptoms are evident, is a predictor of the development of schizophrenia (Owens et al., in press). Reductions in the cerebellum may be associated with reduced activation found in our fMRI study, which has been related to a deficit in the ability of high-risk subjects to increase activation in this area as task difficulty increases (Whalley et al., 2004). Our previous ROI analysis did not find any significant group by time interactions in all high risk vs. controls subjects, (Lawrie et al., 2002) but did find a significant effect in our high risk group with transient or isolated psychotic symptoms in the right temporal lobe ( F 1,64 = 5.4, P = 0.023). The right temporal lobe reduced over time in those high-risk subjects with transient or isolated psychotic symptoms, significantly more than the right temporal lobe reductions in those high-risk subjects without any psychotic symptoms. Similar reductions were also seen in the left temporal lobe in our ROI study, but they did not reach significance. VBM showed reductions in the left temporal lobe within those high-risk subjects with transient or isolated psychotic symptoms. This difference in laterality between our ROI study and the VBM study could be because our VBM study normalises images to a standard template, and this can differentially influence variance and error measurements laterally. However, this difference could also be due to a fundamental difference between volumetric ROI and VBM
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that volumetric ROI measures the volume of a region whereas VBM gives a maximal point of change. It is possible that a volume reduction that is diffuse across a volume would be significant in volumetric measurement, but not give a significant maximal peak in VBM as the reduction could be distributed across too large an area, and the opposite is also possible, that a maximum peak of difference may not appear significant in volumetric measurements, particularly if the volume is large. The present findings do not establish whether or not symptoms follow changes in brain structure, vice versa, or whether symptoms and changes in brain structure occur in unison. They suggest however that people at high risk of schizophrenia for genetic reasons show reductions in grey matter density, and that these reductions are more extensive in those with a liability to develop psychotic symptoms. There were no significant differences at baseline between those who developed symptoms and control subjects, or those who did not develop symptoms, or between those who eventually developed schizophrenia and control subjects, or those who did not fall ill. At baseline, in the high-risk group as a whole compared to the control group, reductions were seen in the left and right anterior cingulate with a trend to a reduction in the left parahippocampal gyrus. Those reductions in GMD, in the 2 to 3 years preceding illness, that were exclusive to the 8 high-risk subjects that had developed schizophrenia, namely in the right cerebellum, the left inferior temporal gyrus and the left uncus, may therefore have lead to the onset of frank psychosis. This indicates the possibility of early detection and potentially effective intervention of this most disabling of disorders, for which current treatments are at best ameliorative.
Acknowledgment This project was funded by a Medical Research Council of Great Britain programme grant.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.neuroimage.2005.01.006.
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Whalley, H.C., Kestelman, J.N., Rimmington, J.E., Kelso, A., Abukmeil, S.S., Best, J.J., Johnstone, E.C., Lawrie, S.M., 1999. Methodological issues in volumetric magnetic resonance imaging of the brain in the Edinburgh High Risk Project. Psychiatry Res. 91, 31 – 44. Whalley, H.C., Simonotto, E., Flett, S., Marshall, I., Ebmeier, K.P., Owens, D.G.C., Goddard, N.H., Johnstone, E.C., Lawrie, S.M., 2004. fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia. Brain 127, 478 – 490. WHO: World Health Organisation, 1992. Tenth Revision of the International Classification of Diseases and Related Health Problems (ICD-10). WHO, Geneva. Wing, J.K., Cooper, J.E., Sartorius, N., 1974. The Description and Classification of Psychiatric Symptoms. An Instruction Manual for the PSE and Catego Systems. Cambridge Univ. Press, Cambridge, UK. Wright, I.C., McGuire, P.K., Poline, J.B., Travere, J.M., Murray, R.M., Frith, C.D., Frackowiak, R.S., Friston, K.J., 1995. A voxel-based method for the statistical analysis of gray and white matter density applied to schizophrenia. NeuroImage 2, 244 – 252. Wright, I.C., Rabe-Hesketh, S., Woodruff, P.W., David, A.S., Murray, R.M., Bullmore, E.T., 2000. Meta-analysis of regional brain volumes in schizophrenia. Am. J. Psychiatry 157, 16 – 25.
Grey matter changes over time in high risk subjects developing schizophrenia Dominic E. Job,T Heather C. Whalley, Eve C. Johnstone, and Stephen M. Lawrie Division of Psychiatry, University of Edinburgh, The Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, Scotland, UK Received 31 March 2004; revised 21 December 2004; accepted 6 January 2005 Available online 3 March 2005 Schizophrenia affects approximately 1% of the population and is associated with reductions in brain volume, but when these are first evident is unknown. Magnetic resonance imaging (MRI) has demonstrated abnormalities of brain structure, particularly of the temporal lobes, in schizophrenia. A study of brain structure in individuals destined to develop schizophrenia, before they do so, is crucial to understanding the illness. We used Voxel Based Morphometry (VBM) to map changes in Grey Matter Density (GMD) in 65 young adults at high risk of schizophrenia, for familial reasons, and 19 healthy young adults, over a period of approximately 2 years. All subjects were antipsychotic naive at both scans. No increases in GMD were found in any of the groups. Within the high-risk group significant declines in GMD were found in the temporal lobes, the right frontal lobe and right parietal lobe. In the control group a decline was found in the right gyrus rectus. No significant differences over time were found between any of the groups. Those individuals at high risk who had transient or isolated psychotic symptoms showed a different spatial pattern of reductions in GMD than those who did not in within group comparisons. In addition, those individuals at high risk who later developed schizophrenia also showed a different spatial pattern of reductions in GMD in the left temporal lobe and right cerebellum, from 2 to 3 years before they were diagnosed. These particular reductions may therefore be able to predict the later onset of schizophrenia. D 2005 Elsevier Inc. All rights reserved. Keywords: Schizophrenia; Grey matter; Brain
Introduction The Edinburgh High Risk Study (EHRS) is the first to prospectively examine the changes in brain structure of people at high risk of schizophrenia for familial reasons, before any individuals fall ill (Johnstone et al., 2000). We compared the changes over time in high risk subjects who had two scans about 2 years apart, in the three groups: well controls (n = 19), high-risk
T Corresponding author. Fax: +44 131 537 6531. E-mail address: [email protected] (D.E. Job). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2005.01.006
subjects without any psychotic symptoms (n = 47), and high-risk subjects with transient or isolated psychotic symptoms (n = 18). Eight of the people from the transient or isolated psychotic symptoms group have subsequently developed schizophrenia, on average 2.34 years after their first scan. Previous cross-sectional imaging studies in schizophrenia found reduced GMD compared to controls, particularly in the temporal lobes, in people with established disease and in the first-episode of illness (Lawrie and Abukmeil, 1998; Lawrie et al., 1999; Shenton et al., 1992; Suddath et al., 1990; Wright et al., 2000). These studies show that structural brain changes are present around the time of onset of psychosis, but the chronology is unknown. However, post-mortem schizophrenia studies have shown mixed findings; some report no change or an increase in GMD in the ventral striatum (Lauer et al., 2001), no change specifically in the amygdala (Chance et al., 2002), whilst others find decreases in GMD (McDonald et al., 2000) in the left parahippocampal gyrus and left fusiform gyrus, similar to those found in MRI studies. The schizophrenic subjects in these post-mortem studies differ greatly from most patients and particularly our high-risk group in age, illness and medication duration, (family history), and are therefore not directly comparable. Further to this, there are differences in the analysis methods used by each approach. Post-mortem studies have to account for individual and regional tissue shrinkage, differences in time to fixation and the fixation period itself, and they measure volume, not maximal points of change, as in VBM. Structural MRI of the brain at first scan in the subjects in this sample revealed that there was lower GMD in the amygdala– hippocampal complex (AHC) in people at high risk, but even less in first-episode patients, compared to healthy controls (Job et al., 2002, 2003; Lawrie et al., 1999, 2001). A subgroup of those highrisk subjects and controls were scanned on a second occasion approximately 2 years later. Some of the high-risk participants had experienced transient or isolated psychotic symptoms during this time. Subsequently, 8 of the high-risk participants went on to develop schizophrenia (Johnstone et al., 2000). We therefore tested a three-part hypothesis in this report. Firstly, we determined whether or not people at high risk of schizophrenia, as a group, show reductions in GMD in the temporal lobes and AHC over time, compared with a control group, that might indicate a general
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and probably genetic effect. Secondly, we examined whether these structures showed greater reductions in GMD in high-risk participants with transient or isolated psychotic symptoms, than in those without any psychotic symptoms. Thirdly, we examined changes over time in the 8 high-risk participants who have since developed schizophrenia, for reductions that are evident preceding illness onset.
Methods Subjects The subjects were recruited for the EHRS (Hodges et al., 1999; Johnstone et al., 2000). A total of 162 high risk subjects who had at least two first or second degree relatives with schizophrenia, were recruited over a period of 4 years. Of this group, 66 people and 19 healthy controls, matched group wise for age, had a structural MRI scan of the whole brain which was repeated after approximately 2 years in the first 5 years of the study. Others were either recruited too late or became ill too soon for two scans to be conducted in this phase. One of the high-risk subject’s scans was lost in a computer malfunction (n = 65). Voxel Based Morphometry (VBM) (Ashburner and Friston, 2000; Wright et al., 1995) was used to compare the groups and changes within groups, specifically examining the amygdala–hippocampal complex and the temporal lobes. This is the first application of VBM to our longitudinal data. Control subjects had been recruited from local youth groups and the social networks of the high risk subjects on the basis that they had no major psychiatric disorders or family history of the same. Details of the two subject groups are presented in Table 1. Ethical approval was obtained from the Psychiatry and Psychology subcommittee of the Lothian Region Ethics Committee and all subjects gave written informed consent. The eight high-risk subjects who developed schizophrenia did so on average 2.34 years (SD 1.02) after their first scans and 0.81 years (SD 0.76) after their second scans. The rationale of the Edinburgh High-Risk Study rests on two pillars (Johnstone et al., 2000). The first is that the risk of schizophrenia in subjects with a family history of the disorder, such as these people have, is at least 10 times that in the general population. The second is that schizophrenia is a disorder with a restricted age of onset particularly so in men. Therefore, for men, if they have not developed the psychosis by the age of 30, the probability is that they will never do so. In women, onsets can be later but by 31st July 2004, the closure date of this second 5-year Table 1 Demographic characteristics of high-risk and control study participants
Age, years (SD)a Male, Female Handedness: Mixed, Left, Right Height (SD) Paternal social class at birth: manual, non-manual, unknownb a
High risk (n = 65)
Control (n = 19)
21.4 (2.7) 34, 31 2, 6, 57
21.0 (2.1) 12, 7 2, 2, 15
172.2 (10.7) 30, 33, 2
173.2 (10.8) 13, 6, 0
Mean age at first assessment. According to the Occupational Classification of the Registrar General [HMSO, 1991].
b
study when the majority of the subjects will be near the age of 30, almost all of those destined to develop schizophrenia will have done so. The age of onset of schizophrenia differs between genders by 3 to 4 years, but it has been reported that this difference is not evident in familial cases, reviewed in Gattaz and Ha¨fner (1999), who conclude that in familial cases such as ours, this differential in age of onset is not apparent. There is, however, no means of establishing who those few who may yet become ill over the next few years may be and no instrument can tell us this. Mental states of the subjects have been assessed every time a scan is conducted (Johnstone et al., 2000). In this study, the high-risk subjects have been divided into those who have never shown possible or definite psychotic symptoms, those who have shown transient or partial psychotic symptoms on at least one occasion but had not developed schizophrenia by 2003 and those who by 2003 had developed schizophrenia. The criteria for these categories are described in Johnstone et al. (2000). Transient psychotic symptoms are symptoms, usually delusions and or hallucinations, which occurred briefly, for minutes or at most a few hours, and which in the case of delusions were not thereafter believed by the subjects or in the case of hallucinations occurred during this brief period and not again. Isolated hallucinations are those which occurred sometimes several times which were brief, for example, a name being called or a phrase repeated but which were not associated with any other misperceptions, delusions or other possibly psychotic psychopathology. Forty percent of both the control and high-risk subjects stated that they had used cannabis at some time and a small number of both groups also used other recreational drugs occasionally. No exclusions were made on the grounds of substance use from either the control group or the high-risk group. Image processing MR brain scanning was performed on a 42 SPE Siemens (Erlangen, Germany) Magnetom operating at 1.0 T. Midline sagittal localisation was followed by two sequences to image the whole brain. The first scan was a double spin echo sequence which gave simultaneous proton density and T2-weighted images (TR = 3565 ms, TE = 20 ms and 90 ms, 31 contiguous 5 mm slices in the Talairach plane, field of view 250 mm 250 mm) to identify any gross brain lesions. The second scan was a three-dimensional Magnetisation Prepared Rapid Acquisition Gradient Echo (MPRAGE) sequence consisting of a 1808 inversion pulse followed by a Fast Low Angle Shot (FLASH) collection (flip angle 128, TR = 10 ms, TE = 4 ms, TI = 200 ms and relaxation delay time 500 ms, field of view 250 mm 250 mm) to give 128 contiguous dslicesT of 1.88 mm thickness. Immediately after each subject’s scan, a large plain test object filled with light oil was scanned in exactly the same place in the coil and in the same orientation as the subject’s head. The test object data was used to correct for inhomogeneity in the radiofrequency coil. Inhomogeneity correction standardises each image to account for scanner inhomogeneity and potential changes in the scanner over time. Repeat scans were conducted on the same scanner, with exactly the same imaging protocol, after approximately 2 years. Our Voxel-Based Morphometry was performed using the SPM99 toolbox (http://www.fil.ion.ucl.ac.uk/spm/spm99.html). A study-specific template and a priori probability maps for grey matter, white matter and cerebral spinal fluid were constructed. Using these study specific templates all of the images in the control
D.E. Job et al. / NeuroImage 25 (2005) 1023–1030
and high-risk group were spatially normalised and segmented, eliminating large-scale differences between the subjects, using a 12-point linear affine transformation only. All of the resulting GMD segments were then smoothed at 12 mm full width at half maximum (FWHM) before being entered into our statistical analysis. It should be noted that GMD refers to the probability of finding grey matter (GM) in a unit volume, not to cell packing or absolute volume. The VBM protocol used in this analysis cannot give an accurate quantification of actual volume reduction. Statistical analysis Group comparisons were performed using a random effects analysis. A repeated measures time groups interaction (ANOVA) statistical model in SPM99 based on the general linear model, was used to replicate the volumetric analysis performed in our previous region of interest (ROI) study (Lawrie et al., 1999, 2001, 2002; Whalley et al., 1999). However, a groups time interaction is not the most useful test for clinical purposes to examine the changes within the high-risk group. In the case of the ANOVA, changes in the control group, significant or not significant, dilute the measurements in the high-risk group, thereby smoothing the measurements and producing a less sensitive test. An alternative method that allows for the differences in spatial patterns of significant changes in the control group and high-risk sub-groups to be taken into account, but not directly compared, in within group comparisons is a masking method not available in our previous volumetric ROI study. This alternative method uses masking to exclude any change over time in the control group (paired F test, P-uncorrected = 0.05), at voxel level, from the changes in the high-risk group ( Pcorrected = 0.05). With this conservative method of masking, groups are not directly compared, but any significant area of change in the second group, the control group in this example, is excluded leaving only changes exclusive to the primary group in the statistical assessment. This statistical technique has previously been used in several functional imaging studies (Cabeza et al., 2004; Critchley et al., 2000; Davis and Johnsrude, 2003; Farrer et al., 2003; Morcom et al., 2003). It can been seen, for example, in Table 2 and Fig. 1, that the left uncus, Brodmann area 20, finding is shown in the masked and unmasked results. The coordinates of these two points differ by less than 2 mm. This shows that the maximal point of change in the uncus in the unmasked contrast has been excluded in the masked contrast, but due to spatially more extensive reductions in those high risk subjects with symptoms, this region is still significantly reduced in the masked within group contrast, and therefore could be useful in a diagnostic test. As the masked paired t test does not include the non-significant changes in the control group, this test cannot be used to conclude that there are greater differences in the high risk group than in the control group, as the null hypothesis of no group differences still cannot be rejected for the control group in the area outside the mask. Since volumetric differences in the AHC and temporal lobes are the most consistent findings in the high risk and schizophrenia literature (Job et al., 2002; Lawrie and Abukmeil, 1998; Lawrie et al., 2001; Shenton et al., 1992; Suddath et al., 1990; Velakoulis et al., 1999; Wright et al., 2000), we further restricted the analyses to voxels within these regions (Small Volume Correction, SVC). These a priori SVCs match the AHC and temporal lobe regions examined in our previous volumetric ROI study. These SVCs (bilateral) were created by manually editing the non-smoothed EHRS T1 template to define the small volume. In order to strengthen
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Table 2 GMD reductions over time in high risk subjects with transient or isolated psychotic symptoms (n = 18, paired t test) Voxel P (corrected)
Talairach coordinates x, y, z (mm)
0.044
37.6,
40.6,
34.1
0.006 0.008 0.033
47.5, 45.5, 46.5,
32.1, 28.1, 12.4,
20.3 1.4 33.9
0.046 0.020 0.050
35.6, 24.8, 21.8,
11.4, 9.2, 14.0,
33.1 29.0 27.1
0.030
26.7,
4.8,
18.3
Points of maximal change with no masking Right Cerebellum, Posterior Lobe, Cerebellar Tonsila Left Fusiform Gyrus, BA 20b Left Superior Temporal Gyrusb Left Inferior Temporal Gyrus, BA 20b Left Uncus, BA 20b Left Uncusc Left Parahippocampal Gyrus, BA 28c Right Parahippocampal Gyrus, Amygdalac
Points of maximal change with masking This mask excludes any areas of significant change in those high risk subjects who do not have any psychotic symptoms (mask: n = 47, F test at P = 0.05 uncorrected threshold) 0.018 36.2, 28.9, 4.3 Left superior lateral surface of hippocampusa 0.000 49.5, 26.5, 25.6 Left fusiform gyrus, BA 20b 0.024 27.7, 9.4, 32.3 Left uncusb 0.029 33.7, 10.4, 34.0 Left uncus, BA 20b 0.037 39.6, 12.5, 36.4 Left inferior temporal gyrus BA 20b 0.050 49.5, 30.9, 3.4 Left superior temporal gyrusb NB BA: Brodmann area. a Corrected at whole brain level. b Temporal lobe small volume correction. c Amygdala hippocampal complex small volume correction.
the validity of our temporal lobes and AHC SVCs, we also applied two SVCs to the occipital lobes, where no changes were expected and none were found. The first occipital lobe SVC closely matched the correction for multiple comparisons of the temporal lobe SVC, and the second closely matched the AHC SVC. Notes concerning the figures In some of the figures, GM reduction appears to be outside of the brain. This is due to averaging and smoothing of the processed images, and the fact that thresholds used for the figures are different from those used in the statistical analysis so that the areas of reduction are clearly visible. No tissue outside the brain should enter into the SPM analysis as all of the images are masked and cleaned to remove non-brain tissue. None of these extra cerebral areas reach statistical significance.
Results In our first comparison, we constructed statistical maps of changes over time in the high-risk and control groups. Using the same statistical analysis (a repeated measures ANOVA, for group time interactions) as used in our previous ROI study, there were no significant differences in GMD changes, over 2 years, between the control and the high-risk group, in keeping with our previous ROI study (Lawrie et al., 2002). However, when we examine the changes over time in the high risk group alone, and then the control
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Fig. 1. GMD reductions over time in those at high risk of schizophrenia who had transient or isolated psychotic symptoms. Green crosshairs indicate reductions in GMD exclusive to those high-risk subjects with symptoms (excluding changes in those high-risk subjects without any psychotic symptoms). Blue crosshairs indicate reductions in those at high risk of schizophrenia with transient or isolated psychotic symptoms that were excluded by the mask. The blue and green crosshairs show the P-corrected maximum points of change as reported in Table 2. (Colour blobs are thresholded at P-uncorrected = 0.005).
group alone, it is evident in the more sensitive VBM analysis that there are many significant changes in the high risk group (n = 65), and high risk sub groups (n = 47, 18 and 8), and only one significant change in the control group (n = 19). These findings were further examined using the within group masking method for their clinical diagnostic potential. Using masking at voxel level, a more spatially specific statistical method not available in our ROI study, previously unreported reductions in GMD over time are seen. We created a mask of any change over time in the control group (paired F test, P-uncorrected threshold = 0.05), at voxel level, and used this voxel mask to remove any significant control group changes from the reductions in the high-risk group (paired t test, P-corrected threshold = 0.05. See the supporting table and supporting figure). It is important to note that the masking contrasts do not examine differences between groups because in this case no information from the control group (the group used to define the mask here) is included in this contrast. The remaining reductions in the masked high-risk group were in the left and right fusiform gyrus, left cingulate gyrus, right inferior parietal lobule, left uncus, left and right middle temporal gyrus, left and right inferior temporal gyrus, right superior temporal gyrus, the left and right parahippocampal gyrus and the lateral border of the left amygdala. However, this voxel masking method has the problem that significant changes in the high-risk group can be excluded completely by this means. The changes over time in the highrisk group without the use of masking are therefore also given to facilitate comparison with our previous ROI volumetric study (Lawrie et al., 2002). Without the exclusion of the significant control group changes, reductions in GMD in the high-risk group
are seen in the right cingulate gyrus, left and right cerebellum, the right occipital lobe, right uncus and left superior temporal gyrus. Exclusive masking can also affect the volume to surface area ratio of a volume and therefore alter the correction for multiple comparisons; hence, there are three exclusive points of GMD reduction in Table 3, but only one non-exclusive point. The two additional points seen in the masked contrast did not reach significance in the unmasked contrast, but due to the reduced volume of the masked contrast there were fewer multiple
Table 3 GMD reductions over time in high risk subjects who have developed schizophrenia (n = 8, paired t test) Voxel P (corrected) 0.05
Talairach coordinates x, y, z (mm) 24.8,
10.2,
29.0
Points of maximal change with no masking Left uncus, Brodmann Area 28a
Points of maximal change with masking This mask excludes any areas of significant change in those people at high risk who have transient or isolated psychotic symptoms, but have not developed schizophrenia (mask: n = 10, F test at P = 0.005 uncorrected) 0.044 40.6, 44.6, 38.1 Right cerebellumb 0.043 51.1, 16.1, 31.2 Left inferior temporal gyrus, Brodmann area 20c 0.05 24.6, 10.2, 28.9 Left uncus, Brodmann area 28a a b c
Amygdala hippocampal complex small volume correction. Corrected at whole brain level. Temporal lobe small volume correction.
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comparisons and therefore a slightly less strict correction was applied. In our second comparison of the high-risk subjects with transient or isolated psychotic symptoms (n = 18, paired t test, P-corrected threshold = 0.05. Table 2, Fig. 1), we found reductions over time in the right cerebellum, left fusiform gyrus, left uncus, left superior temporal gyrus, left inferior temporal gyrus, left and right parahippocampal gyrus and the right amygdala. If we exclude any significant changes in the high-risk group who did not have any psychotic symptoms, using a mask (n = 47, paired F test, P-uncorrected threshold = 0.05), from the reductions in those who do have transient or isolated psychotic symptoms, we still see reductions in the left fusiform gyrus, left uncus, the left superior and inferior temporal gyri and the left superior lateral surface of the hippocampus. Our previous ROI study found a significant reduction in the right temporal lobe between the high-risk group with transient or isolated psychotic symptoms and those high-risk subjects without any psychotic symptoms (ANOVA), but we found no difference between these groups in this VBM study (ANOVA). Those high-risk subjects with transient or isolated psychotic symptoms did not have severe enough symptoms to warrant them being diagnosed as having a formal psychiatric illness, or to notably impair their everyday functioning. In our third comparison of those high risk subjects that have developed schizophrenia at their second scan (n = 3, of whom 1 is male) or since their second scan (n = 5, of whom 3 are male) (total n = 8, paired t test, P-corrected threshold = 0.05. Table 3, Fig. 2), excluding any significant changes seen in those high-risk subjects who had transient or isolated psychotic symptoms but did not develop schizophrenia (mask: n = 10, paired F test, P-uncorrected threshold = 0.05), we see reductions in GMD in the left inferior temporal gyrus, left uncus and the right cerebellum. In the control group alone, one reduction in GMD was found in the right gyrus rectus at 0.004 P-corrected (n = 19, paired t test, P-corrected threshold = 0.05. Talairach coordinates: x = 4.0, y = 20.8, z = 24.8, Fig. 3). There were no increases in GMD over time in any of the groups. The differences in group sizes could potentially confound our results, although it should be noted that we found reductions in the sub-sample of 8 high risk subjects that have developed schizophrenia. A brief review of previous results At baseline those subjects at high-risk (n = 146) were subtly different from controls (n = 36) (Job et al., 2003). Subjects at high-
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Fig. 3. GMD reductions over time in the 19 control subjects. The blue crosshair shows the P-corrected maximum point of change. (Colour blobs are thresholded at P-uncorrected = 0.0005). NB The colour bars in the figures show the Z scores corresponding to colours in the images. The numbers at the bottom left of each brain slice shows the height of the slice on the z axis in MNI coordinates. Crosshairs are accurate to the nearest 2 mm.
risk showed reduced grey matter in left and right anterior cingulate ( P-corrected b 0.05) with a trend to a difference in the left parahippocampal gyrus ( P-corrected b 0.1). The high-risk subjects showed no increases compared to controls. At baseline, those at high risk who did not eventually fall ill (n = 130) were not different to those who fell ill (n = 16), nor were there any associations of transient or isolated psychotic symptoms at that time (n = 101 nonsymptomatic vs. n = 42 with transient or isolated psychotic symptoms; 3 did not have clinical interviews at that time).
Discussion We did not find evidence to support the first part of our hypothesis, namely a reduction in temporal lobe volumes in all high-risk individuals as compared to controls. However, using exclusive masking, a statistical technique used more often in functional MRI (Cabeza et al., 2004; Critchley et al., 2000; Davis and Johnsrude, 2003; Farrer et al., 2003; Morcom et al., 2003), the within group analyses do provide information that may be useful for early diagnostic purposes. This masking technique was not applicable to our previous ROI volumetric data. Our findings do not support the second part of our hypothesis, in that the left and right temporal lobes was reduced in volume in high-risk subjects with transient or isolated psychotic symptoms, compared to those high-risk subjects without psychotic symptoms. Finally, the third part of our hypothesis is supported since the 8 high-risk subjects
Fig. 2. GMD reductions over time in those 8 people in the high-risk group who have since developed schizophrenia. Green crosshairs indicate reductions in GMD in those 8 people who have developed schizophrenia, excluding any change in those 10 high risk subjects who had transient or isolated psychotic symptoms, but did not develop schizophrenia (Colour blobs are thresholded at P-uncorrected = 0.001). The green crosshairs show the P-corrected maximum point of change as reported in Table 3.
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who now have schizophrenia showed GMD reductions in the right cerebellum and left temporal lobe 2 years before developing schizophrenia. In contrast, lower GMD at baseline in the high-risk subjects compared to healthy controls did not predict schizophrenia in the larger number of subjects who were only scanned once. These results suggest that subjects at high risk of schizophrenia for genetic reasons have trait and presumably genetically mediated reductions in cortical volumes in early adulthood as seen in the baseline analysis, and that changes are greater, as seen in the previous ROI study, in those who also have a liability to transient or isolated psychotic symptoms. Most people with this dintermediate phenotypeT will not however develop schizophrenia. This is associated with still further subtle changes. We have analysed the data by transient or isolated psychotic symptoms and by psychosis per se so that these results apply to those who develop schizophrenia and to those with transient or isolated psychotic symptoms, and because the pathophysiology of schizophrenia is poorly understood. The symptomatic subjects had transient partial or isolated delusions and hallucinations, but most were working and not functionally impaired, and none were thought to be ill. The diagnosis of schizophrenia was made when these psychotic symptoms were sufficiently severe or sustained to justify such categorisation in terms of PSE/Catego (Wing et al., 1974) and ICD10 (WHO, 1992) criteria. In the control group alone, a reduction in GMD over time is seen in the right gyrus rectus, bordering the orbital frontal gyrus. We have examined all scans for artefacts, but found none. Sowell et al. (2003) showed that GMD reduces the right gyrus rectus between the ages of 10 and 20 years, 20 and 30 years, and 30 and 40 years, and attributes this loss of GM to a gain in myelination, with an increase in GM between the ages of 60 and 90 years, in normal controls. Giedd et al. (1999) also found a decline in GM in the frontal lobe during post-adolescence (11– 22 years). In contrast, Sowell et al. (2003) found that a decrease in normal temporal lobe GMD occurs later, from an approximate age of 50 years. It may be that we did not find a similar GMD reduction in the gyrus rectus in the high-risk subjects because of greater than normal variability in the high-risk group, but there could be genetic reasons. We found bilateral reductions in the high risk group as a whole, mainly in the temporal lobes, but also in the cingulate and anterior cingulate as well as unilateral reductions in the right frontal lobe, right inferior parietal lobe and right cerebellum. Those high-risk subjects who had experienced transient or isolated psychotic symptoms over the years covered by this report showed reductions mainly in the left temporal lobe, and also the right cerebellum and right amygdala. When excluding any change in those high-risk subjects without any psychotic symptoms from the symptomatic group, we only found changes in the left temporal lobe and right cerebellum. Considering these data from the point of view of clinical prediction, this suggests that those at high risk as a whole suffer bilateral reductions in the temporal lobes, but those at high risk who go on to develop symptoms show more loss in the left temporal lobe and right cerebellum, and in some of them 2 years before the onset of psychosis. The left uncus finding in those 8 high-risk subjects who have developed schizophrenia is marginal since it is only picked up by the AHC SVC. This SVC is derived from the unsmoothed average image, which is intended to encompass the entire AHC and therefore includes some surrounding structures. This finding is evidently part of the edge of a larger area of GMD reduction in the temporal lobe, which is mostly outside the AHC. Findings in this
small group of 8 individuals are limited due to the small number of scans. Nevertheless, differences were found, in keeping with our hypothesis, and have not previously been reported in high-risk subjects or this long before illness onset. Thompson et al. (2001) found that temporal lobe grey matter loss was absent early, but became pervasive later, in early onset schizophrenia (aged 13.9 F 0.8 years at first scan). Left medial temporal lobe loss is also apparent between the prodromal phase, and first episode of psychosis, specifically in subjects who had sought psychiatric attention (Pantelis et al., 2003). Velakoulis et al. (2002) found reduced volume on the left side only, in patients at first presentation with schizophrenia, and that reduced grey matter in the right medial temporal lobe (anterior hippocampus, uncus, parahippocampal gyrus), medial cerebellar and bilateral anterior cingulate, developed in relation to the increasing duration of their illness. Our findings in anti-psychotic naive high-risk subjects, taken together with these other relevant findings in medicated prodromal and first presentation subjects (Pantelis et al., 2003; Thompson et al., 2001; Velakoulis et al., 2002), suggest that those at high risk of schizophrenia have reduced grey matter volumes, predominantly bilaterally in the temporal lobes, and that those who go on to develop symptoms have more severe reductions in the left temporal lobe 2 years before the onset of psychosis, a loss which could continue until the onset of psychosis. Subjects may then suffer further reductions in the right temporal lobes following their first onset. These lateralised findings have precedence (Crow, 2002), but brain torque and other asymmetric structures may account for some of this apparent lateralisation. Automated normalisation methods, such as those currently used in VBM could be negatively affected by brain torque as there may be differences in brain torque between our groups and this could lead to false-positives due to shape differences, not GMD differences. In the 8 psychotic subjects, the left uncus and temporal cortex reduction may relate to impairments in emotional expression recognition, which in turn may foster anxiety and paranoia (Dilger et al., 2003; Gray and McNaughton, 2000). It is therefore of interest that psychopathological assessments in the high-risk sample as a whole have shown that anxiety, years before psychotic symptoms are evident, is a predictor of the development of schizophrenia (Owens et al., in press). Reductions in the cerebellum may be associated with reduced activation found in our fMRI study, which has been related to a deficit in the ability of high-risk subjects to increase activation in this area as task difficulty increases (Whalley et al., 2004). Our previous ROI analysis did not find any significant group by time interactions in all high risk vs. controls subjects, (Lawrie et al., 2002) but did find a significant effect in our high risk group with transient or isolated psychotic symptoms in the right temporal lobe ( F 1,64 = 5.4, P = 0.023). The right temporal lobe reduced over time in those high-risk subjects with transient or isolated psychotic symptoms, significantly more than the right temporal lobe reductions in those high-risk subjects without any psychotic symptoms. Similar reductions were also seen in the left temporal lobe in our ROI study, but they did not reach significance. VBM showed reductions in the left temporal lobe within those high-risk subjects with transient or isolated psychotic symptoms. This difference in laterality between our ROI study and the VBM study could be because our VBM study normalises images to a standard template, and this can differentially influence variance and error measurements laterally. However, this difference could also be due to a fundamental difference between volumetric ROI and VBM
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that volumetric ROI measures the volume of a region whereas VBM gives a maximal point of change. It is possible that a volume reduction that is diffuse across a volume would be significant in volumetric measurement, but not give a significant maximal peak in VBM as the reduction could be distributed across too large an area, and the opposite is also possible, that a maximum peak of difference may not appear significant in volumetric measurements, particularly if the volume is large. The present findings do not establish whether or not symptoms follow changes in brain structure, vice versa, or whether symptoms and changes in brain structure occur in unison. They suggest however that people at high risk of schizophrenia for genetic reasons show reductions in grey matter density, and that these reductions are more extensive in those with a liability to develop psychotic symptoms. There were no significant differences at baseline between those who developed symptoms and control subjects, or those who did not develop symptoms, or between those who eventually developed schizophrenia and control subjects, or those who did not fall ill. At baseline, in the high-risk group as a whole compared to the control group, reductions were seen in the left and right anterior cingulate with a trend to a reduction in the left parahippocampal gyrus. Those reductions in GMD, in the 2 to 3 years preceding illness, that were exclusive to the 8 high-risk subjects that had developed schizophrenia, namely in the right cerebellum, the left inferior temporal gyrus and the left uncus, may therefore have lead to the onset of frank psychosis. This indicates the possibility of early detection and potentially effective intervention of this most disabling of disorders, for which current treatments are at best ameliorative.
Acknowledgment This project was funded by a Medical Research Council of Great Britain programme grant.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.neuroimage.2005.01.006.
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