Brain, Vol. 124, No. 5, 882-892,
May 2001
© 2001 Oxford University Press
Neuropathological abnormalities in schizophrenia: evidence from magnetization transfer imaging
1 NMR Research Unit, Institute of Neurology, 2 Imperial College School of Medicine, Charing Cross Campus, London, UK and 3 Department of Psychiatry, Gilead Hospital and MRI Unit, Mara Hospital, Bielefeld, Germany
Correspondence to:
Dr J. Foong, Department of Neuropsychiatry, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK E-mail: j.foong@ion.ucl.ac.uk
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Abstract |
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Post-mortem and structural brain imaging studies in schizophrenia have reported macroscopic changes such as global and regional cortical volume reductions, but it has been more difficult to characterize the histopathological changes that underlie these abnormalities. Magnetization transfer imaging (MTI), a novel MRI technique, more sensitive to subtle or early neuropathological changes than conventional MRI, provides a quantitative measure of macromolecular structural integrity represented by the magnetization transfer ratio (MTR). In this study, we used MTI to examine 25 patients with schizophrenia compared with 30 age-matched controls. A voxel-based analysis of the MTR maps revealed widespread MTR reductions in the cortex unrelated to volume reduction, predominantly in the frontal and temporal regions, in the schizophrenic patients when compared with controls. MTR reductions in bilateral parieto-occipital cortex and the genu of the corpus callosum were associated with the severity of negative symptoms in the schizophrenic patients. However, MTR changes were not related to other clinical variables of age, duration of illness and current dose of antipsychotic medication. This study demonstrates that MTR abnormalities in the cortex can be detected in chronic schizophrenia that may reflect subtle neuropathological changes involving neurones or neuronal processes. Longitudinal studies are needed to determine whether these abnormalities are related to disease progression or other disease manifestations such as cognitive changes.
magnetization transfer imaging; magnetization transfer ratio; schizophrenia; neuropathological abnormalities
MTI = magnetization transfer imaging; MTR = magnetization transfer ratio; NART = National Adult Reading Test; PANSS = Positive and Negative Syndrome Scale; ROI = region of interest; SPM = statistical parametric mapping
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Introduction |
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Structural brain abnormalities have been reported extensively in schizophrenia, but the neural systems involved have not been well characterized. A recent meta-analysis of structural MRI studies (Wright et al., 2000
) has confirmed the presence of global structural changes, namely cerebral volume reduction and ventricular enlargement as well as regional volume abnormalities, particularly in bilateral medial temporal lobe structures. Volumetric losses may be accounted for to a significant degree by reduction of cortical volume (Zipursky et al., 1992; Harvey et al., 1993; Lim et al., 1996). Other studies have suggested the presence of regional reductions in grey matter, particularly in the frontal (Schlaepter et al., 1994; Sullivan et al., 1998; Goldstein et al., 1999; Wright et al., 1999), temporal lobes (Pearlson et al., 1997; Lawrie and Abukmiel, 1998; Wright et al., 1999) and medial temporal structures such as the hippocampus (Suddath et al., 1990; Shenton et al., 1992) and amygdala (Brier et al., 1992; Marsh et al., 1994; Wright et al., 2000).
The macroscopic findings of global and regional volume reductions in schizophrenia have been confirmed by some post-mortem studies (Pakkenberg, 1987; Falkai et al., 1988; Bogerts et al., 1990). However, it has been more difficult to characterize the histopathological changes that underlie these macroscopic abnormalities. It is well recognized that a number of methodological problems such as small sample size, effects of ageing, poor clinical documentation and differences in histological techniques have limited such studies.
Structural brain abnormalities detected on conventional MRI are gross by definition, with loss of volume or focal lesions indicating an obvious pathological process. More subtle abnormalities, which may nevertheless have functional significance, cannot be detected by conventional MRI. This has led to the application of novel MRI techniques, such as magnetization transfer imaging (MTI), which have the potential for providing more neuropathological information in vivo and may be more sensitive to subtle or early neuropathological changes. MTI allows the visualization of protons tightly bound to macromolecular structures, such as myelin and cell membranes in white matter, that are essentially invisible to conventional MRI because of their very short relaxation times. The exchange of magnetization between bound protons and free water is represented by the magnetization transfer ratio (MTR) which provides a quantitative measure of macromolecular structural integrity. Large reductions in MTR have been reported in neurological conditions where there is significant myelin loss, such as multiple sclerosis (Dousset et al., 1992; Gass et al., 1994; Thorpe et al., 1995), progressive multifocal leucoencephalopathy (Dousset et al., 1997) and central pontine myelinolysis (Silver et al., 1996). Post-mortem studies in multiple sclerosis have confirmed that MTR abnormalities in white matter are also related to axonal loss (Mottershead et al., 1998; van Waesberghe et al., 1998). Importantly, MTR appears to be sensitive to subtle changes in tissue and has been able to detect abnormalities in normal appearing white matter in multiple sclerosis that are undetected on conventional MRI (Fillipi et al., 1995). Abnormalities of MTR in grey matter, however, have not been studied as extensively as in white matter, and therefore their neuropathological correlates remain to be determined. There are, on the other hand, a priori reasons to believe that MTR may be sensitive enough to detect abnormalities in cortical neuronal processes suggested by previous histopathological studies to be central in the neuropathology of schizophrenia (Selemon et al., 1998; Glantz et al., 2000).
The purpose of this study therefore was to use MTR to explore and characterize further the neuropathological abnormalities in vivo in patients with schizophrenia. We were interested in examining changes in cortical cytoarchitecture using MTR given that we previously have found largely normal white matter in this cohort (Foong et al., 2000) using a region of interest (ROI) methodology. In the present study, we adopted a voxel-based analysis that allowed us to examine the brain globally without any a priori assumptions of regional abnormalities and to explore the relationship of structural abnormalities to clinical features. To our knowledge, our study is the first to use this technique and methodology in the study of schizophrenia.
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Methods |
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Subjects
Twenty-five patients (19 males, six females) who fulfilled the DSM-IV criteria for schizophrenia were recruited from the Bethlem and Maudsley Hospitals for this study. Their mean age was 37.3 years (range 25–46 years). The mean duration of psychiatric symptoms was 14.3 years (range 3–22 years) and all patients were on antipsychotic medication at the time of the study (mean dosage 341.2 mg per day equivalent to chlorpromazine; British National Formulary, 2000).
Thirty healthy controls (22 males, eight females) with a mean age of 35.1 years (range 25–49 years) were selected to match the patient group as closely as possible with respect to age, gender and paternal social class (Goldthorpe, 1974). Any subject with a history of neurological or systemic illness, head injury, drug abuse or alcohol intake of more than 30 units a week was excluded from the study. Informed consent was obtained from all subjects and the study was approved by the ethics committees of the Maudsley Hospital and Institute of Neurology.
Clinical assessments
The subscales for positive and negative symptomatology of the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) were used to provide a measure of schizophrenic symptoms during the week prior to assessment. Each scale measures seven symptoms (positive scale—delusions, conceptual disorganization, hallucinatory behaviour, excitement, grandiosity, suspiciousness and hostility; negative scale—blunted affect, emotional withdrawal, poor rapport, social withdrawal, difficulty in abstract thinking, lack of spontaneity or flow of conversation, and stereotyped thinking). Each symptom is ranked 1–7 depending on severity, and the total scores range from 7 to 49.
The National Adult Reading Test (NART; Nelson and Willison, 1991) provided an estimate of pre-morbid IQ and was used to match the controls to the patients.
The Annett questionnaire (Annett, 1970) was administered to assess hand preference.
MRI
All subjects had a MRI scan which was performed on a GE Signa 1.5 tesla scanner using a standard quadrature head coil. The total scanning time was ~60 min and the following sequences were used. (i) T2-weighted and proton density images were acquired initially using a dual echo sequence TE [(echo time), 15/90 ms; TR (repetition time), 3000 ms, 28 contiguous 5-mm axial slices, 256 x 256 pixel image matrix, 24 x 24 cm2 FOV (field of view)]. (ii) Imaging using a spin echo-based magnetization transfer sequence (TE 30/80 ms, TR 1720 ms, 28 contiguous 5-mm axial slices, 256 x 128 pixel image matrix, 24 x 24 cm2 FOV) was acquired with and without a saturation pulse. The saturation pulse was a 16 ms, 23.2 uT Hamming appodized three lobe sinc pulse, applied 1 kHz from water resonance.
MTIs were co-registered intrinsically with the proton density and T2-weighted images. MTR was calculated on a pixel by pixel basis from the formula:
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MRI and clinical assessment were performed on the same day.
Data analysis
Data were analysed on a Sun SPARC workstation (Sun Microsystems, Mountain View, Calif., USA) using SPM96 (Wellcome Department of Cognitive Neurology, London, UK) (Friston et al., 1995b). The following steps were used to process and analyse the data.
Spatial normalization
The T2 images were registered into a standard (Talairach) space in a three-stage process using a modified version (Symms et al., 1996) of the Automated Image Registration software (Woods et al., 1992). (i) The T2-weighted images, including the skull, were registered to the MNI (Montreal Neurological Institute) T2-weighted average brain that is provided with SPM96. (ii) An automated program was then used to mask the registered images with a version of the MNI atlas where most of the skull had been removed from the T2-weighted image. (iii) The skull-stripped T2-weighted image was then registered to the skull-stripped T2-weighted MNI atlas.
Following this process, the two registration parameter files were combined and applied to the MTR images, transforming them into Talairach space. The skull was removed by masking with the skull-stripped MNI atlas.
Smoothing
Images were smoothed using a 10 mm FWHM (full width half maximum) Gaussian filter (SPM96) to improve the signal to noise ratio and to allow for intersubject anatomical variability.
Statistical analysis
Following the above processing steps, a group comparison of MTR changes between schizophrenic patients and controls was performed. The estimates were compared using two contrasts, and the grey matter threshold was set at 40%. For each voxel, this analysis detected the probability of MTR changes (i.e. a reduction or increase in MTR) in schizophrenic patients relative to controls. The resulting set of voxel values for each contrast constitutes a statistical parametric map (SPM) of the t statistic (SPM{t}). The SPM maps were transformed to normal distribution SPM{z} from which P values were derived. We used a statistical threshold of z = 3.09, P < 0.001 to identify areas of significant differences in MTR between the groups at the cluster (group of voxels) and individual voxel level. To correct for multiple comparisons, the resulting foci were characterized in terms of spatial extent k (Friston et al., 1995a). This correction describes the probability that a region of the observed size could have occurred by chance over the entire volume analysed (i.e. a corrected P value). The corrected P value selected was P < 0.05.
The duration of the scanning procedure precluded us from obtaining three-dimensional volume data. In order to determine whether atrophy contributed significantly to MTR changes, we analysed the proton density weighted images from the magnetization transfer sequence which are sensitive to volumetric changes. A group comparison of the proton density images was performed using the same process as for MTR, to identify areas of significant reduction in signal intensity that would suggest reduction of cortical volume.
Segmentation
To determine whether the areas of MTR changes were located in white or grey matter, we used the a priori grey and white matter probability maps provided with SPM99 to compare with the normalized MR images. A threshold of 50% on the white matter probability map was chosen to identify areas more likely to be in white matter than grey matter.
Clinical covariates
Covariate analysis using SPM was also performed on the MTR data. Clinical variables of age, duration of illness, current dose of antipsychotic medications (dose equivalent to chlorpromazine) and PANSS scores were used as covariates to determine whether MTR changes were related to these variables and whether these correlations were localized to specific brain regions.
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Results |
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The clinical and demographic information is summarized in Table 1
. There were no significant differences in age, gender and paternal social class between the schizophrenic patients and controls. There was also no significant group difference in mean pre-morbid IQ as estimated from the NART scores which were available for 19 patients and 19 controls (110.7 and 113.2, respectively). All subjects were right handed apart from one schizophrenic patient and two controls.
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Most patients scored higher on the negative than positive subscales of the PANSS. The mean total score was 18.6 (range 9–33) for negative symptoms and 11.6 (range 7–24) for positive symptoms. These scores suggest that positive and negative symptoms were only mild to moderate in severity for our group of patients.
Group differences in MTR
Group analysis in SPM comparing half the controls with the other half revealed no significant MTR changes at the level of smoothing, grey matter threshold and level of significance that we used. These same levels of smoothing and grey matter thresholds were used to examine differences between patients and controls. Group analysis comparing the schizophrenic patients with controls revealed bilateral areas of significant MTR reduction at the cluster level in schizophrenic patients in inferior and middle frontal, and inferior and middle temporal and superior occipital gyri (Fig. 1). Of these areas, the left inferior frontal, right superior occipital and right inferior temporal were also significant at the voxel level. Using the segmented white matter map, we were able to identify that the areas of MTR reduction were predominantly in the cortex, particularly in frontal and temporal regions. The MTR reductions extended into the white matter only in the temporal lobes, specifically in the middle temporal gyri (Fig. 2).
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Group differences in structural MRI
The same levels of smoothing and grey matter thresholds used for the MTR data were applied to the proton density images. Group analysis of the proton density weighted images in SPM revealed some areas of significantly reduced signal intensity, suggestive of cortical volume loss or atrophy in the left inferior frontal cortex in the schizophrenic group (Fig. 3
). These areas were far less extensive than the cortical areas of reduced MTR.
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Relationship between MTR and clinical variables
Covariate analysis using SPM revealed no significant MTR reductions with increasing age in either the patient or control group, although there was a trend for the changes being more widespread in the patients compared with controls prior to correction for multiple comparisons. In the schizophrenic group, duration of illness and current dose of antipsychotic medications (chlorpromazine dose equivalents) were not related to MTR. Greater MTR reductions at the cluster level were observed in bilateral temporo-occipital cortex, left inferior parietal and the genu of the corpus callosum, with increasing severity of negative, but not positive symptoms. This suggests that some symptom clusters may be related to focal MTR changes (Fig. 4
). Using the more stringent voxel level analysis, the left parietal and temporo-occipital areas remained significantly related to the severity of negative symptoms, but only a trend towards significance was observed for the other areas.
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Discussion |
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The results of our study suggest that there are diffuse bilateral cortical abnormalities in schizophrenia, predominantly in the frontotemporal cortex. These abnormalities only extend into the white matter in the temporal areas. This study provides the first evidence that MTR is a useful tool to detect subtle neuropathological abnormalities where little cortical volume reduction is evident.
The predominant localization of MTR reduction to the frontotemporal regions is in keeping with the results reported by others (Weinberger et al., 1992; Wright et al., 1999; Sigmundsson et al., 2001) using conventional MRI, that have suggested that schizophrenia involves mainly frontotemporal networks. The interest of our work, however, rests on the finding that MTR abnormalities are far more extensive than those detected with conventional MRI.
It is difficult to be specific about the nature of the changes in the cortex as the histopathological counterparts of MTR changes in grey matter have not been explored fully. Histopathological studies in schizophrenia have reported neuronal abnormalities (Falkai et al., 1988; Benes et al., 1991, 1998; Akbarian et al., 1993; Pakkenberg, 1993; Selemon et al., 1995, 1998; Jonsson et al., 1997; Zaidel et al., 1997), although the findings have been inconsistent. Recent evidence also suggests that abnormalities can be localized to specific cortical layers such as a reduction in neuronal size restricted to layer IIIc in the prefrontal cortex (Rajkowska et al., 1998). Further indirect support for neuronal abnormalities in schizophrenia comes from magnetic resonance spectroscopy studies that have reported a reduction in N-acetylaspartate, considered to be a marker of neuronal or axonal integrity, in the temporal lobes (Renshaw et al., 1995; Yurgelun-Todd et al., 1996) and particularly the hippocampus (Maier et al., 1996; Bertolini et al., 1996; Lim et al., 1998).
Although the histopathological findings in schizophrenia have been inconsistent, a consensus is beginning to emerge from studies using stereological techniques. Thus, contrary to earlier reports of reduced neuronal density in the cortex (Falkai et al., 1988; Benes et al., 1991; Akbarian et al., 1993), more recent studies using stereological techniques (Pakkenberg et al., 1993; Selemon et al., 1998) have found an increase in neuronal density in the presence of cortical volume reduction. These findings have given rise to the suggestion that abnormalities in the neuropil, which is comprised of neuronal processes such as dendrites and synapses, may be more significant than neuronal loss in schizophrenia and at least partly account for the cortical changes (Selemon et al., 1998; Glantz et al., 2000). Dendritic abnormalities have been detected with Golgi staining, such as a reduction in spine density in layer III pyramidal cells in prefrontal cortex (Glantz and Lewis, 1997) and subicular apical dendrites of the hippocampus (Rosoklija et al., 2000). Other studies using indirect methods by measuring immunoreactivity have reported either a reduction (Arnold et al., 1991) or an increase (Cotter et al., 2000) in microtubule-associated protein (MAP2), a dendritic marker, and reduction in synaptophysin, a synaptic marker, in the hippocampus (Harrison et al., 1998; Young et al., 1998) and dorsal lateral prefrontal cortex (Glantz et al., 1997). Others (Perrone-Bizzozero et al., 1996) have reported an increase in presynaptic growth-associated phosphoprotein (GAP-43) in frontal and occipital cortices, suggesting a disruption in synaptic organization. Our results are therefore compatible with these neuropathological findings of subtle abnormalities in the cortex involving neurones or neuronal processes in schizophrenia. It is likely that such abnormalities may disrupt the neural circuitry and result in altered connectivity. This would support the theory that schizophrenia is a disorder of brain connectivity which has originated mainly from findings of abnormal functional connectivity, particularly in frontotemporal regions, in schizophrenic patients (Frith et al., 1995; McGuire et al., 1996). More recently, it has been suggested that anatomical connections are also disrupted in schizophrenia. Some studies have reported abnormal correlations between regional brain volumes in the frontotemporal (Woodruff et al., 1997b) or thalamocortical (Portas et al., 1998) regions. Others have suggested that the anatomical connections are abnormal on a microscopic level in schizophrenia and that any alteration in the dendritic arbor may affect interneuronal connectivity (Selemon et al., 1999).
The temporal white matter MTR reductions in the schizophrenic patients confirm the findings of our previous study using an ROI analysis in the same group of patients which detected reduced MTR in temporal but not other regions of white matter (Foong et al., 2000). These temporal white matter MTR changes are likely to reflect a focal disruption of axonal or myelin integrity. This would result in a disruption of axonal connections and thus provides further support for the theory of altered anatomical connectivity in schizophrenia. Our finding of focal white matter abnormalities is in contrast to recent reports of a widespread reduction of anisotropy in white matter (Lim et al., 1999) or prefrontal white matter (Bushbaum et al., 1998) using diffusion tensor imaging. One possible reason for this is that the MTR changes in other areas of white matter may be more subtle than in the temporal lobes and were not detected with our technique and sample size. Therefore, despite the sensitivity of the technique, our results do not exclude the possibility of more subtle abnormalities in other regions of white matter.
We chose to use a voxel-based automated analysis, SPM96, to examine group MTR differences in grey and white matter in this study. Although this widely available software tool was developed originally for functional imaging, it has been shown recently to be sensitive in the analysis of structural MRI abnormalities (Woermann et al., 1999). This technique allowed us to perform a global analysis and avoided the a priori bias of using an ROI approach as in our previous report (Foong et al., 2000). In addition, it also enabled us to study cortical abnormalities, something that would have been extremely difficult with an ROI methodology due to partial volume effects. Normalization of the images was performed to increase the sensitivity for detecting focal changes by reducing the anatomical variability between subjects and, by using a reliable segmentation process, we were able to separate grey and white matter abnormalities. However, we were not able to detect any significant age-related MTR changes in either group in this study, in contrast to previous reports of subtle age-related MTR reductions in white matter in a healthy population using an ROI methodology (Silver et al., 1997). This may have been due to the narrower age range of our subjects compared with the other study. For the SPM statistics, we used the cluster level rather than the voxel level of significance, as histograms of a sample of our data incorporating white and grey matter on a given slice resembled a normal distribution. This satisfies the recently suggested criteria for the use of cluster size to assess significance in SPM which is only considered appropriate if the data are distributed normally (Ashburner and Friston, 2000). Furthermore, the lack of significant MTR changes between our two groups of controls, using the same level of smoothing, grey matter threshold and level of significance, suggests that the differences in MTR between schizophrenics and controls in this study are likely to be biologically significant.
An intriguing finding of our study is the association of MTR reduction in the left parietal, bilateral temporo-occipital cortex and genu of the corpus callosum with negative symptoms. This would lend some support to previous reports that negative symptoms are related to focal structural abnormalities (Gunther et al., 1991; Woodruff et al., 1997a; Tibbo et al., 1998). The localization of the specific cortical areas where MTR abnormalities were more prominent in those with negative symptoms was somewhat unexpected. The same applies to the fact that MTR differences between patients and controls in these areas were not especially prominent. The fact that our patients only had mild to moderate negative symptoms may be a possible explanation. Thus, in the six patients who had total negative symptoms scores >24 (midpoint of the range of total scores), further analysis revealed a non-significant trend towards more widespread cortical MTR reductions when compared with the rest of the group. Therefore, our findings do not exclude the possibility that MTR changes may be present in other regions such as the frontal lobes, more commonly associated with the presence of negative symptoms (Baare et al., 1999; Sanfilipo et al., 2000).
The patients in our study had a long duration of illness and had been on antipsychotic medication for many years. However, it seems unlikely that the effect of antipsychotic medication is a significant confounding factor. Although an unreliable measure, we did not observe any association between MTR abnormalities and the current dose of medication. In addition, there is little evidence accruing from neuropathological studies that cortical abnormalities can be attributed to antipsychotic medication (Harrison, 1999).
Several limitations to our study should be considered. The sample size in this study was small and it may not be possible to generalize our findings to other schizophrenic populations. We also did not examine gender differences in MTR in this study, as there were considerably fewer females than males in both groups. A recent meta-analysis found little evidence of gender differences in regional and global cerebral volumes in schizophrenia (Wright et al., 2000), but less is known about gender differences in the histopathological changes. It is of interest that recent histopathological studies in normal subjects, albeit in small samples, have reported that males have greater neuronal density than females and, reciprocally, females have increased neuropil in the presence of similar cortical thickness (de Courten-Myers, 1999; Rabinowicz et al., 1999). This has led to speculation that this may explain the greater incidence of Alzheimer's disease, characterized by neuronal loss, in females. Therefore, it is possible that this may also explain the greater incidence of schizophrenia in males if schizophrenia proves to be a disease involving the neuropil of which females have a greater reserve. A further limitation to our study was the lack of three-dimensional volume MRI data which would have been more accurate in determining cerebral volume reduction than the proton density images. The proton density images were selected in preference to T2-weighted images as they have a higher signal to noise ratio and provide clearer discrimination of tissue from the CSF. It remains possible that our approach underestimated the true extent of the cortical volume reduction, but it is also very unlikely that the MTR reductions in our patients were related solely to cortical atrophy as more widespread changes on the proton density images would have been detected.
This cross-sectional study has demonstrated that MTR abnormalities can be detected in chronic schizophrenia that may reflect subtle neuropathological changes undetected by conventional MRI. Longitudinal studies are needed to establish whether these MTR abnormalities are present at the onset of the illness or if they progress, how they may relate to other disease manifestations, such as cognitive changes, and their prognostic significance. Furthermore, future studies applying this technique to other major psychiatric illnesses are needed to determine whether these findings are specific to schizophrenia.
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Acknowledgments |
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We wish to thank members of the NMR Research Unit, Institute of Neurology for their assistance. We also thank all the patients and control subjects who participated in this study. This research was funded by the Wellcome Trust. M.A.R. was partly funded by the SCARFE Trust.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE Jr, Jones EG. Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Arch Gen Psychiatry 1993; 50: 178–87.
Annett MA. A classification of hand preference by association analysis. Br J Psychol 1970; 61: 303–21.[Web of Science][Medline]
Arnold SE, Lee VM-Y, Gur RE, Trojanowski JQ. Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia. Proc Natl Acad Sci USA 1991; 88: 10850–4.
Ashburner J, Friston KJ. Voxel-based morphometry—the methods. [Review]. Neuroimage 2000; 11: 805–21.[Web of Science][Medline]
Baare WF, Hulshoff Pol HE, Hijman R, Mali WP, Viergever MA, Kahn RS. Volumetric analysis of frontal lobe regions in schizophrenia: relation to cognitive function and symptomatology. Biol Psychiatry 1999; 45: 1597–605.[Web of Science][Medline]
Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 1991; 48: 996–1001.
Benes FM, Kwok EW, Vincent SL, Todtenkopf MS. A reduction of non-pyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 1998; 44: 88–97.[Web of Science][Medline]
Bertolino A, Nawroz S, Mattay VS, Barnett AS, Duyn JH, Moonen CT, et al. Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry 1996; 153: 1554–63.
Bogerts B, Falkai P, Haupts M, Greve B, Ernst S, Tapernon-Franz U, et al. Post-mortem volume measurements of limbic system and basal ganglia structures in chronic schizophrenics. Initial results from a new brain collection. Schizophr Res 1990; 3: 295–301.[Web of Science][Medline]
Breier A, Buchanan RW, Elkashef A, Munson RC, Kirkpatrick B, Gellad F. Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex and caudate structures. Arch Gen Psychiatry 1992; 49: 921–6.
Buchsbaum MS, Tang CY, Peled S, Gudbjartsson H, Lu D, Hazlett EA, et al. MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia. Neuroreport 1998; 9: 425–30.[Web of Science][Medline]
Cotter D, Wilson S, Roberts E, Kerwin R, Everall IP. Increased dendritic MAP2 expression in the hippocampus in schizophrenia. Schizophr Res 2000; 41: 313–23.[Web of Science][Medline]
de Courten-Myers GM. The human cerebral cortex: gender differences in structure and function. J Neuropathol Exp Neurol 1999; 58: 217–26.[Web of Science][Medline]
Dousset V, Grossman RI, Ramer KN, Schnall MD, Young LH, Gonzalez-Scarano F, et al. Experimental allergic encephalomyelitis and multiple sclerosis: lesion characterization with magnetization transfer imaging. Radiology 1992; 182: 483–91.
Dousset V, Armand JP, Lacoste D, Mieze S, Letenneur L, Dartigues JF, et al. Magnetization transfer study of HIV encephalitis and progressive multifocal leukoencephalopathy. AJNR Am J Neuroradiol 1997; 18: 895–901.[Abstract]
Falkai P, Bogerts B, Rozumek M. Limbic pathology in schizophrenia: the entorhinal region—a morphometric study. Biol Psychiatry 1988; 24: 515–21.[Web of Science][Medline]
Filippi M, Campi A, Dousset V, Baratti C, Martinelli V, Canal N, et al. A magnetization transfer imaging study of normal appearing white matter in multiple sclerosis. Neurology 1995; 45: 478–82.
Foong J, Maier M, Barker GJ, Brocklehurst S, Miller DH, Ron MA. In vivo investigation of white matter pathology in schizophrenia with magnetization transfer imaging. J Neurol Neurosurg Psychiatry 2000; 68: 70–4.
Friston KJ, Ashburner J, Frith CD, Poline JB, Heather JD, Frackowiak RS. Spatial registration and normalization of images. Hum Brain Mapp 1995a; 3: 165–89.
Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frackowiak RS. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995b; 2: 189–10.
Frith CD, Friston KJ, Herold S, Silbersweig D, Fletcher P, Cahill C, et al. Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry 1995; 167: 343–9.
Gass A, Barker GJ, Kidd D, Thorpe JW, MacManus DG, Brennan A, et al. Correlation of magnetization transfer ratio and clinical disability in multiple sclerosis. Ann Neurol 1994; 36: 62–7.[Web of Science][Medline]
Glantz LA, Lewis DA. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia: regional and diagnostic specificity. Arch Gen Psychiatry 1997; 54: 943–52.
Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.
Goldstein JM, Goodman JM, Seidman LJ, Kennedy DN, Makris N, Lee H, et al. Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging. Arch Gen Psychiatry 1999; 56: 537–47.
Goldthorpe JH, Hope K. The social grading of occupations: a new approach and scale. Oxford: Clarendon Press; 1974.
Gunther W, Petsch R, Steinberg R, Moser E, Streck P, Heller H, et al. Brain dysfunction during motor activation and corpus callosum alterations in schizophrenia measured by cerebral blood flow and magnetic resonance imaging. Biol Psychiatry 1991; 29: 535–55.[Web of Science][Medline]
Harrison PJ. The neuropathological effects of antipsychotic drugs. [Review]. Schizophr Res 1999; 40: 87–99.[Web of Science][Medline]
Harrison PJ, Eastwood SL. Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia. Lancet 1998; 352: 1669–73.[Web of Science][Medline]
Harvey I, Ron MA, Du Boulay G, Wicks D, Lewis SW, Murray RM. Reduction of cortical volume in schizophrenia on magnetic resonance imaging. [Review]. Psychol Med 1993; 23: 591–604.[Web of Science][Medline]
Jonsson SA, Luts A, Guldberg-Kjaer N, Brun A. Hippocampal pyramidal cell disarray correlates negatively to cell number: implications for the pathogenesis of schizophrenia. Eur Arch Psychiatry Clin Neurosci 1997; 247: 120–7.[Web of Science][Medline]
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–76.
Lawrie SM, Abukmeil SS. Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies. [Review]. Br J Psychiatry 1998; 172: 110–20.
Lim KO, Sullivan EV, Zipursky RB, Pfefferbaum A. Cortical gray matter volume deficits in schizophrenia: a replication. Schizophr Res 1996; 20: 157–64.[Web of Science][Medline]
Lim KO, Adalsteinsson E, Spielman D, Sullivan EV, Rosenbloom MJ, Pfefferbaum A. Proton magnetic resonance spectroscopic imaging of cortical gray and white matter in schizophrenia. Arch Gen Psychiatry 1998; 55: 346–52.
Lim KO, Hedehus M, Moseley M, de Crespigny A, Sullivan EV, Pfefferbaum A. Compromised white matter tract integrity in schizophrenia inferred from diffusion tensor imaging. Arch Gen Psychiatry 1999; 56: 367–74.
Maier M, Ron MA, Barker GJ, Tofts PS. Proton magnetic resonance spectroscopy: an in vivo method of estimating hippocampal neuronal depletion in schizophrenia. Psychol Med 1995; 25: 1201–9.[Web of Science][Medline]
Marsh L, Suddath RL, Higgins N, Weinberger DR. Medial temporal lobe structures in schizophrenia: relationship of size to duration of illness. Schizophr Res 1994; 11: 225–38.[Web of Science][Medline]
McGuire PK, Frith CD. Disordered functional connectivity in schizophrenia [editorial]. Psychol Med 1996; 26: 663–7.[Web of Science][Medline]
Mottershead JP, Thornton JS, Clemence M, Scaravilli F, Newcombe J, Cuzner ML, et al. Correlation of spinal cord axonal density with post mortem NMR measurements in multiple sclerosis and controls [abstract]. Proceedings of International Society for Magnetic Resonance in Medicine 6th meeting 1998. p. 2163.
Nelson H, Willison J. National Adult Reading Test (NART). 2nd edn. Windsor (UK): NFER-Nelson; 1991.
Pakkenberg B. Post-mortem study of chronic schizophrenic brains. Br J Psychiatry 1987; 151: 744–52.
Pakkenberg B. Total nerve cell number in neocortex in chronic schizophrenics and controls estimated using optical disectors. Biol Psychiatry 1993; 34: 768–72.[Web of Science][Medline]
Pearlson GD, Barta PE, Powers RE, Menon RR, Richards SS, Aylward EH, et al. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol Psychiatry 1997; 41: 1–14.[Web of Science][Medline]
Perrone-Bizzozero NI, Sower AC, Bird ED, Benowitz LI, Ivins KJ, Neve RL. Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc Natl Acad Sci USA 1996; 93: 14182–7.
Portas CM, Goldstein JM, Shenton ME, Hokama HH, Wible CG, Fischer I, et al. Volumetric evaluation of the thalamus in schizophrenic male patients using magnetic resonance imaging. Biol Psychiatry 1998; 43: 649–59.[Web of Science][Medline]
Rabinowicz T, Dean DE, Petetot JM, de Courten-Myers GM. Gender differences in the human cerebral cortex: more neurons in males; more processes in females. J Child Neurol 1999; 14: 98–107.
Rajkowska G, Selemon LD, Goldman-Rakic PS. Neuronal and glial somal size in the prefrontal cortex. Arch Gen Psychiatry 1998; 55: 215–24.
Renshaw PF, Yurgelun-Todd DA, Tohen M, Gruber SA, Cohen BM. Temporal lobe proton magnetic resonance spectroscopy of patients with first episode psychosis. Am J Psychiatry 1995; 152: 444–6.
Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, et al. Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders. Arch Gen Psychiatry 2000; 57: 349–56.
Sanfilipo M, Lafargue T, Rusinek H, Arena L, Loneragan C, Lautin A, et al. Volumetric measure of the frontal and temporal lobe regions in schizophrenia. Relationship to negative symptoms. Arch Gen Psychiatry 2000; 57: 471–80.
Schlaepter TE, Harris GJ, Tien AY, Peng LW, Lee S, Federman EB, et al. Decreased regional cortical gray matter volume in schizophrenia. Am J Psychiatry 1994; 151: 842–8.
Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. [Review]. Biol Psychiatry 1999; 45: 17–25.[Web of Science][Medline]
Selemon LD, Rajkowska G, Goldman-Rakic PS. Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 1995; 52: 805–18.
Selemon LD, Rajkowska G, Goldman-Rakic PS. Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three dimensional, stereologic counting method. J Comp Neurol 1998; 392: 402–12.[Web of Science][Medline]
Shenton ME, Kikinis R, Jolesz FA, Pollak SD, LeMay M, Wible CG, et al. Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. N Engl J Med 1992; 327: 604–12.[Abstract]
Sigmundsson T, Suckling J, Maier M, Williams SCR, Bullmore ET, Greenwood K, et al. Structural abnormalities in frontal, temporal and limbic regions and interconnecting white matter tracts in schizophrenia. Am J Psych 2001; 158: 234–43.
Silver NC, Barker GJ, MacManus DG, Miller DH, Thorpe JW, Howard R. Decreased magnetisation transfer ratio due to demyelination: a case of central pontine myelinolysis [letter]. J Neurol Neurosurg Psychiatry 1996; 61: 208–9.
Silver NC, Barker GJ, MacManus DG, Tofts PS, Miller DH. Magnetisation transfer ratio of normal brain white matter: a normative database spanning four decades of life. J Neurol Neurosurg Psychiatry 1997; 62: 223–8.
Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR. Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 1990; 322: 789–94.[Abstract]
Sullivan EV, Lim KO, Mathalon D, Marsh L, Beal DM, Harris D, et al. A profile of cortical gray matter volume deficits characteristic of schizophrenia. Cereb Cortex 1998; 8: 117–24.
Symms MR, Wang L, Barker GJ, Tofts PS. Detection of serial changes in transient ischaemic attack using image registration [abstract]. Proceedings of the International Society for Magnetic Resonance in Medicine 4th meeting. New York; 1996. p. 558.
Thorpe JW, Barker GJ, Jones SI, Moseley I, Losseff, MacManus DG, et al. Magnetisation transfer ratios and transverse magnetisation decay curves in optic neuritis: correlation with clinical findings and electrophysiology. J Neurol Neurosurg Psychiatry 1995; 59: 487–92.
Tibbo P, Nopoulos P, Arndt S, Andreason NC. Corpus callosum shape and size in male patients with schizophrenia. Biol Psychiatry 1998; 44: 405–12.[Web of Science][Medline]
Van Waesberghe JH, van Walderveen MA, de Groot CJ, Ravid R, Lycklama a Nijeholt GJ, Kamphorst W, et al. Post mortem correlation between axonal loss, MTR and hypointensity on T1 SE in MS. Proceedings of the International Society for Magnetic Resonance in Medicine 6th meeting 1998. p. 1334.
Weinberger DR, Berman KF, Suddath RL, Torrey EF. Evidence of dysfunction of a prefrontal–limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry 1992; 149: 890–7.
Woermann FG, Free SL, Koepp MJ, Ashburner J, Duncan JS. Voxel-by-voxel comparison of automatically segmented cerebral gray matter—a rater-independent comparison of structural MRI in patients with epilepsy. Neuroimage 1999; 10: 373–84.[Web of Science][Medline]
Woodruff PW, Phillips ML, Rushe T, Wright IC, Murray RM, David AS. Corpus callosum size and inter-hemispheric function in schizophrenia. Schizophr Res 1997a; 23: 189–96.[Web of Science][Medline]
Woodruff PW, Wright IC, Shuriquie N, Russouw H, Rushe T, Howard RJ, et al. Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation. Psychol Med 1997b; 27: 1257–66.[Web of Science][Medline]
Woods RP, Cherry SR, Mazziotta JC. Rapid automated algorithm for aligning and reslicing PET images. J Comput Assist Tomogr 1992; 16: 620–33.[Web of Science][Medline]
Wright IC, Sharma T, Ellison ZR, McGuire PK, Friston KJ, Brammer MJ, et al. Supra-regional brain systems and the neuropathology of schizophrenia. Cereb Cortex 1999; 9: 366–78.
Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000; 157: 16–25.
Young CE, Arima K, Xie J, Hu L, Beach TG, Falkai P, et al. SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb Cortex 1998; 8: 261–8.
Yurgelun-Todd DA, Renshaw PF, Gruber SA, Ed M, Waternaux C, Cohen BM. Proton magnetic resonance spectroscopy of the temporal lobes in schizophrenics and normal controls. Schizophr Res 1996; 19: 55–9.[Web of Science][Medline]
Zaidel DW, Esiri MM, Harrison PJ. The hippocampus in schizophrenia: lateralized increase in neuronal density and altered cytoarchitectural asymmetry. Psychol Med 1997; 27: 703–13.[Web of Science][Medline]
Zipursky RB, Lim KO, Sullivan EV, Brown BW, Pfefferbaum A. Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry 1992; 49: 195–205.
Received September 18, 2000. Revised December 18, 2000. Accepted January 5, 2001.
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