Department of Psychiatry, University of Edinburgh
Department of Medical and Radiological Sciences, University of Edinburgh
Department of Psychiatry, University of Edinburgh
Wellcome Trust Clinical Research Facility, University of Edinburgh
Department of Psychiatry, University of Edinburgh
Correspondence: J. Burns, Department of Psychiatry, University of Edinburgh; Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK
Declaration of interest The study was supported by a grant from the Stanley Medical Research Institute.
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ABSTRACT |
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Aims To investigate the structural integrity of frontotemporal and frontoparietal white matter tracts in schizophrenia.
Method Thirty patients with DSMIV schizophrenia and thirty matched control subjects underwent DTMRI and structural MRI. Fractional anisotropy an index of the integrity of white matter tracts was determined in the uncinate fasciculus, the anterior cingulum and the arcuate fasciculus and analysed using voxel-based morphometry.
Results There was reduced fractional anisotropy in the left uncinate fasciculus and left arcuate fasciculus in patients with schizophrenia compared with controls.
Conclusions The findings of reduced white matter tract integrity in the left uncinate fasciculus and left arcuate fasciculus suggest that there is frontotemporal and frontoparietal structural disconnectivity in schizophrenia.
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INTRODUCTION |
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METHOD |
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Procedures
Subjects underwent whole-brain structural MRI and DT-MRI using a GE Signa
LX 1.5 T (General Electric, Milwaukee, WI, USA) clinical scanner. The
structural MRI imaging consisted of a T1-weighted gradient-echo volumetric
sequence followed by a dual-echo fast spin-echo sequence designed to give
contiguous axial proton density and T2-weighted magnetic resonance images. In
the whole-brain DTMRI examination, sets of axial diffusion-weighted
single-shot echo-planar (DWEP) images (bmin=0 and
bmax=1000 s/mm2) were collected with diffusion
gradients applied sequentially along six non-collinear directions
(Basser & Pierpaoli, 1998).
Five acquisitions consisting of a baseline T2-weighted echo-planar image and
six DWEP images a total of 35 images were collected per
slice position. Other acquisition parameters were 31 contiguous axial slices
of 5 mm thickness, a field of view of 240 x 240 mm, an acquisition
matrix of 128 x 128 (zero filled to 256 x 256), a repetition time
of 10 s and an echo time of 98.8 ms. The set of five component DWEP
images for each gradient direction was averaged to give seven high
signal-to-noise ratio images for each slice. Eddy-current-induced artefacts
were then corrected in the six averaged DWEP images
(Bastin, 1999). Within each
voxel the six elements of the apparent diffusion tensor of water (D)
were estimated from the signal intensities measured in the DWEP images
(Basser et al, 1994).
The directional dependence of water diffusion, or diffusion anisotropy, can be
expressed as a scalar quantity, the fractional anisotropy, which varies from
zero (diffusion equal in all directions) to unity (diffusion purely
unidirectional). Maps of the T2-weighted signal intensity and fractional
anisotropy were generated on a voxel-by-voxel basis and converted into Analyze
format (Mayo Foundation, Rochester, MN, USA).
Analysis
The image processing methods were based on an optimised voxel-based
morphometry technique (Good et
al, 2001) and implemented in SPM99
(http://www.fil.ion.ucl.ac.uk/spm/).
Both data preprocessing and the statistical parametric map analysis were
performed by investigators blinded to subject status (i.e. whether patient or
control). The T2-weighted echo-planar images acquired in the DTMRI
examination were segmented to native space using internal spatial
normalisation. The white matter segments were then spatially normalised to
white matter a priori probability maps to derive
white-matter-specific warps. The specific warps were then applied to the raw
fractional anisotropy maps and the raw T2-weighted images. The spatially
normalised T2-weighted images were segmented into grey matter, white matter
and cerebrospinal fluid. The spatially normalised fractional anisotropy images
and white matter segments were then smoothed with a 12-mm isotropic full width
at half-maximum Gaussian filter. Two random- effects analyses using a
measurement of brain volume as a confound were constructed, the first for the
fractional anisotropy images and the second for the white matter segments. The
small-volume correction tool supplied with SPM99 was used to define a
priori hypothesised volumes for the uncinate and arcuate fasciculi and
the anterior cingulum. Small-volume correction is a technique where one can
perform a region-of-interest analysis in SPM99 (with all the associated
benefits of the statistical parametric map method). Based upon the a
priori hypothesis, coordinates were selected that represented the
midpoints of the structures that we wished to investigate. In this case,
coordinates for the three tracts were selected from the Talairach Atlas and
converted to Montreal Neurological Institute (MNI) coordinates. The MNI
coordinates for the small-volume correction were: 11.0 mm radius spheres
centred at [±32, +5, -21] for the uncinate fasciculus, [±31,
+11, -23] for the arcuate fasciculus and [±10, +5, -34] for the
anterior cingulum. In other words, three spheres of 11.0-mm radius were
centred on these coordinates, and mean functional anisotropy values for each
voxel within the spheres were compared between the two study groups. The
11.0-mm radius rendered the smallest spheres possible for a valid statistical
inference in this particular statistical parametric map analysis.
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RESULTS |
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No significant differences were detected in the small-volume corrections placed over the right arcuate fasciculus, the right uncinate fasciculus or the right and left anterior cingulum. There were no volumetric differences between the groups in the white matter segments derived from the T2-weighted images.
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DISCUSSION |
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Diffusion tensor MRI
Diffusion tensor MRI is a relatively new structural imaging modality that
measures the three-dimensional mobility of brain water molecules in
vivo (Basser et al,
1994). In this technique, the apparent diffusion tensor of water
(D) is calculated for each voxel in an image from sets of
diffusion-weighted magnetic resonance images. Owing to the presence of axonal
membranes, myelin sheaths and micro-filaments, water molecules diffuse
preferentially along axons rather than across them. Thus, within coherent,
ordered white matter structures, the mobility of water is greatest in the
principal direction of the fibre tract. This directional dependence of water
diffusion is termed diffusion anisotropy and can be represented
by a range of scalar parameters, or diffusion anisotropy indices, derived from
D (Basser, 1995). The
most common diffusion anisotropy index is the fractional anisotropy, which
varies from zero (diffusion equal in all directions) to unity (diffusion
purely unidirectional). Extensive in vivo and in vitro
experiments on various non-myelinated neuronal fibres, axons with large
axoplasmic spaces and neurons in which fast axonal transport has been
inhibited indicate that the primary determinant of white matter anisotropic
diffusion is the dense packing of axonal membranes, with myelin playing a
secondary role (Beaulieu & Allen,
1994). Any pathological factors that alter the structural
organisation and/or reduce the density of axonal membranes might be expected
to cause a reduction in diffusion anisotropy values compared with those
measured in normal brain. Thus, fractional anisotropy is taken to be a marker
of neuronal integrity, with high fractional anisotropy values indicating
healthy, intact white matter tracts
(O'Sullivan et al,
2001).
Previous DTMRI studies in schizophrenia
Previous studies have reported reduced fractional anisotropy in both
frontal white matter and the splenium of the corpus callosum on exploratory
analyses (Buchsbaum et al,
1998; Lim et al,
1999; Agartz et al,
2001; Foong et al,
2002). Some have used statistical parametric mapping methods of
analysis and the results are varied
(Buchsbaum et al,
1998; Agartz et al,
2001; Foong et al,
2002). None has used the small-volume correction tool and future
studies may benefit from using this technique. A study by Kubicki
(Kubicki et al, 2002)
is interesting in terms of our own findings and indeed the asymmetry
hypothesis (Crow, 1995).
Presumably motivated by a similar interest in frontotemporal connections, they
looked at diffusion anisotropy in the uncinate fasciculus and found a
group-by-side interaction in the patient group, although the fractional
anisotropy was reduced on the left side and their smaller number of subjects
may have reduced the power to find statistically significant differences.
Structural basis of functional disconnectivity
Although there is evidence for a disturbance of the functional relationship
between frontal and temporal and frontal and parietal lobes in schizophrenia,
it is not clearly understood whether white matter connections between these
regions are structurally abnormal. With DTMRI, however, it was possible
to investigate this hypothesis. Data from both human and primate dissection
studies suggested that these association tracts may include the uncinate
fasciculus, the anterior cingulum and the superior longitudinal or arcuate
fasciculus (Dejerine, 1895;
Petrides & Pandya, 1988). In this study we applied current analysis techniques to fractional anisotropy
maps obtained from DTMRI data to test the hypothesis that these
specific frontotemporal and frontoparietal white matter tracts would be
disrupted in patients with schizophrenia. Such a disruption would manifest
itself as a reduction in fractional anisotropy values in patients with
schizophrenia compared with controls.
The arcuate fasciculus is a major association tract connecting large parts of the frontal association cortices with parietal and temporal association areas (Dejerine, 1895). It also forms the main connection between Wernicke's and Broca's language areas. Our finding of reduced neuronal integrity in the left arcuate fasciculus supports the notion that schizophrenia is a disorder of large-scale neurocognitive networks rather than specific regions and, as others suggest, pathological changes in this disorder should be sought at the supra-regional rather than regional level (Sigmundsson et al, 2001). Both structural and functional abnormalities of frontoparietal networks have been described in schizophrenia (Schlaepfer et al, 1994; Honey et al, 2002), and may constitute a basis for the wide range of cognitive functions impaired in the disorder, such as selective attention, language processing and attribution of agency.
The uncinate fasciculus is the largest of the three fibre tracts connecting the frontal and temporal lobes, and dissection studies have demonstrated that the bulk of these fibres connect the orbital and medial prefrontal cortex (including anterior cingulate cortex) to the amygdala, entorhinal cortex and rostral superior temporal gyrus (Petrides & Pandya, 1988; Morris et al, 1999). These frontal and temporal cortical regions show grey matter volume changes in many structural imaging studies of schizophrenia (Lawrie & Abukmeil, 1998; Wright et al, 2000) and possibly the greatest structural decrements. During early brain development, ingrowing association fibres linking these frontal and temporal cortices could encounter abnormal termination sites and form aberrant connections in the superficial layers. Pruning of aberrant connections during the second and third decades of life could lead to impoverished dendritic arborisation rather than neuronal depopulation (Harrison, 1999). Such a mechanism may possibly account for grey and white matter loss and reduced inter-correlations of these volumes (Wible et al, 1995; Woodruff et al, 1997), as well as our findings of reduced neuronal integrity in the uncinate fasciculus. A recent post-mortem study of the uncinate fasciculus in schizophrenia merits particular consideration (Highley et al, 2002). Right-greater-than-left asymmetry of the uncinate fasciculus was demonstrated in both patients and controls, with no significant differences in asymmetry between the two groups. A possible interpretation, in terms of our own findings, is that the different techniques are examining different aspects of uncinate morphology. The study by Highley et al (2002) may yield information about fibre number and density, whereas our study is detecting differences in neuronal integrity as the uncinate tracts disperse near their termination in the temporal lobe.
Methodological issues
Our findings are unlikely to be artefactual, given that the third tract
that we studied the anterior cingulum showed no differences in
fractional anisotropy. The relatively large numbers of subjects involved
provide adequate power and suggest generalisability. The two groups were well
matched and the automated methods of analysis optimised power and minimised
error. The voxel-based morphometry analysis of white matter volume showed no
differences between the two groups, supporting the view that the reductions in
diffusion anisotropy in the left uncinate fasciculus and left arcuate
fasciculus can be attributed to impaired neuronal integrity rather than to
volumetric differences.
Most of our patients were on psychotropic medication at the time of scanning but it does not seem likely that this potential confounder could account for the findings because any effects would not have been localised. Smoothing with a 12-mm Gaussian filter promotes the detection of 12-mm differences in spatial extent but may miss smaller differences. This could explain our failure to find effects on the right side and in the anterior cingulum. The anterior cingulum is a particularly slender tract and therefore more liable to partial volume effects in statistical parametric map analysis of this structure. It may be, of course, that the anterior cingulum is normal in schizophrenia and that the uncinate fasciculus and arcuate fasciculus are the main structures implicated in frontotemporal and frontoparietal disconnectivity.
Our findings of reduced neuronal integrity in the left uncinate fasciculus and left arcuate fasciculus suggest structural disconnectivity in schizophrenia and also, we would argue, suggest that aberrant connectivity is a wider feature of fibre tracts linking the prefrontal to posterior cortices. Future studies might seek to elucidate further the exact relationship between the anatomical findings of dysconnectivity and the clinical symptoms of schizophrenia.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication July 16, 2002. Revision received December 5, 2002. Accepted for publication December 9, 2002.
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