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Alterations of white matter connectivity in first episode schizophrenia
www.elsevier.com/locate/ynbdi Neurobiology of Disease 22 (2006) 702 – 709
Alterations of white matter connectivity in first episode schizophrenia Andrea Federspiel,a,1 Stefan Begre´,b,*,1 Claus Kiefer,a,c Gerhard Schroth,c Werner K. Strik,a and Thomas Dierksa a
University Hospital of Clinical Psychiatry, Department of Psychiatric Neurophysiology, Berne, Switzerland Department of General Internal Medicine, Division of Psychosomatic Medicine, Inselspital Bern, University of Berne, CH-3010 Berne, Switzerland c Inselspital Berne, Department of Neuroradiology, University of Berne, Berne, Switzerland b
Received 22 August 2005; revised 12 December 2005; accepted 22 January 2006 Available online 19 April 2006
Cerebral disconnectivity due to white matter alterations in patients with chronic schizophrenia assessed by diffusion tensor imaging has been reported previously. The aim of this preliminary study is to investigate whether cerebral disconnectivity can be detected as early as the first episode of schizophrenia. Intervoxel coherence values were compared by voxel-based t test in 12 patients with first episode schizophrenia and 12 age- and gender-matched control groups. We detected 14 circumscribed significant clusters ( P < 0.02), 3 of them with higher, and 11 of them with lower IC values for patients with schizophrenia than for healthy control groups. We interpret these white matter alterations in different regions to be disconnected fiber tracts already present early in schizophrenic disease progression. D 2006 Elsevier Inc. All rights reserved. Keywords: Intervoxel coherence; Fractional anisotropy; Diffusion tensor imaging; Gray matter; White matter; First episode schizophrenia
Introduction Schizophrenia has been described as a disorder of disrupted connectivity in the fronto-thalamo-striato-cerebellar circuit (Andreasen et al., 1998). The basis of impaired connectivity may be subtle gray and white matter lesions, as described by several investigators (Shenton et al., 2001). Diffusion tensor imaging (DTI) is a relatively new approach to assessing tissue structure and geometry at a microscopic level. It measures diffusion-driven displacements of molecules during their random path along axonal fibers, expressed as fractional anisotropy (FA) or intervoxel coherence (IC) ranging from 0 (isotropic medium) to 1 (fully anisotropic medium). IC guarantees a very robust signal-to-noise ratio and considers the degree of collinearity between the diffusion
* Corresponding author. Fax: +41 31 382 11 84. E-mail address: [email protected] (S. Begre´). 1 These authors contributed equally to this work. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ - see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2006.01.015
tensor of the reference voxel and the adjacent voxels (Pierpaoli and Basser, 1996; Pfefferbaum et al., 2000); in literature, IC is also labeled as Coherence Index (Deutsch et al., 2005). IC is a measure similar to FA (Klingberg et al., 1999, 2000). It is related to FA value; high IC value indicates both the local strength of FA and the agreement of fiber direction in neighboring voxels (Deutsch et al., 2005). In both studies, the main orientation of major fiber tracts important for reading and spelling were reported using FA and IC measures. Previous studies have shown a reduced FA in schizophrenia (Agartz et al., 2001; Ardekani et al., 2003; Buchsbaum et al., 1998; Burns et al., 2003; Foong et al., 2000; Hubl et al., 2004; Kubicki et al., 2003, 2005; Kumra et al., 2004; Lim et al., 1999; Minami et al., 2003; Okugawa et al., 2004; Sun et al., 2003; Wang et al., 2004). Only one study reported augmented FA in circumscribed tracts of the brain in hallucinating, chronic schizophrenic patients as compared with FA in healthy control groups (Hubl et al., 2004). Using FA in first episode schizophrenia, two studies found no differences compared to healthy controls in the hippocampus (Begre et al., 2003) or the splenium and genu of corpus callosum (Price et al., 2005). Using IC, two studies of the same group compared amygdale and entorhinal regions in chronic schizophrenia patients to healthy controls (Kalus et al., 2005a,b). To our knowledge, IC has never been used to investigate white matter in first episode schizophrenic patients. Several studies suggest that schizophrenia is a progressive disease accompanied by loss of gray and white matter volume (Cahn et al., 2002; Gogtay et al., 2004; Velakoulis et al., 2002). However, it is not clear whether changes in white matter structure exist from childhood, prior to the first psychotic symptoms, or develop during disease progression. To investigate whether previously described anisotropy changes of white matter in chronic schizophrenia are present at the beginning of the schizophrenic course, we measured IC as an indication of connectivity in 12 first episode psychosis patients. We used 12 ageand gender-matched subjects as the control group. From previous results of studies in chronic schizophrenia using FA, we expected to find clusters of reduced IC in corpus callosum, cingulum, main white matter fascicles, as well as in frontal, temporal, and occipital white matter regions.
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Materials and methods
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of view [FOV] = 256 mm, voxel dimension = 1.0 mm 1.0 mm 1.0 mm).
Subjects DTI recording and processing Twelve patients (8 men and 4 women, mean age 23.4 years T 3.0 years SD, range 18.1 – 28.7 years, all right-handed) hospitalized with their first episode of schizophrenia, diagnosed according to ICD-10 diagnosis criteria (Bramer, 1988) were pair matched by gender and age (T6 months) with 12 healthy volunteers (mean age of 23.2 years T 3.1 years SD, range 17.6 – 28.5 years, all righthanded). Patients with schizophrenia were recruited from the first episode ward of the University Hospital of Clinical Psychiatry in Berne; the control group consisted of normal volunteers from the region. Patients and their relatives were questioned about the development of psychotic symptoms, substance abuse, and any other psychiatric or medical conditions. All patients had at least first-rank symptoms, but one lacked auditory hallucinations. Three patients, including the one without auditory hallucinations, reported sporadic cannabis use. At the time of the measurements, the average duration of illness was 115.7 days (SD T 91.0 days, range 14 – 270 days), and the average duration of medication was 10.5 days (SD T 11.0 days, range 0 – 35 days). Three patients were medicated with risperidone, 3 with olanzapine, 2 with quetiapine, 1 with amisulpride, and 2 with both haloperidol and risperidone. One patient was not medicated. None of the control subjects had a history of major medical or neurological disorders, substance abuse, or other psychiatric diseases, or received psychotropic medication before hospitalization. All subjects gave written informed consent, and the study received approval from the local ethical committee. For measurements in the magnetic resonance imaging (MRI) scanner, subjects received no specific instructions other than to relax and keep their head still. The use of restraining foam pads minimized head motion. MRI recording MRI imaging was performed on a 1.5-T standard clinical MRI scanner (Siemens Vision, Erlangen, Germany), using the standard radio-frequency head coil. First, a high-resolution three-dimensional data set covering the whole brain was collected for each subject through a 3D magnetization-prepared rapid-acquisition gradient echo (MP-RAGE) sequence. In all, 192 scans were accumulated (TR = 6 s, TE = 95 ms, matrix size = 256 256 voxels, field
For diffusion-weighted imaging, a single-shot spin-echo – echoplanar imaging (SE-EPI) sequence was acquired in the same session. Gradient amplitudes and duration were chosen so as to enable detection of tissue-dependent diffusion coefficients by the signal attenuation: G = 22 mT/m, duration TE = 20 ms, intergradient time interval = 40.00 ms, TR = 3000 ms. In total, 12 axial continuous slices (5 mm slice thickness, no gap) were acquired. The matrix size = 64 64 voxels, field of view [FOV] = 240 mm, voxel dimension = 3.75 mm 3.75 mm 5.0 mm. The diffusion sensitizing gradients were applied simultaneously on two axes around the 180- pulse at b = 1800 s/mm2/axis along 6 noncollinear directions: ( G x , G y, G z ) =pffiffi[(1, 0, 1), (1, 0, 1), ffi (0, 1, 1), (0, 1, 1), (1, 1, 0), (1, 1, 0)]/ 2. This gradient scheme was chosen to minimize acquisition time, so as to include as many schizophrenic patients as possible in the study. This, despite suggestions that the optimal gradient scheme may include more than 6 gradient directions (Jones, 2004; Jones et al., 1999). Additionally, one image was acquired with no gradients applied. Eddy-current corrections were included. Images were smoothed using a Gaussian filter with a FWHM of 7.5 mm. To test for nonnormality of the residuals, the Shapiro – Wilk test was computed for each voxel of each cluster. With the Shapiro – Wilk test, the null hypothesis is that residuals follow an normal distribution, i.e., if the P value is greater than alpha value of 0.05, then the null hypothesis will not be rejected (Jones et al., 2005). The calculation and diagonalization of the diffusion tensor were based on the multivariate regression approach (Basser et al., 1994). Six independent elements of the diffusion tensor were extracted (Basser and Pierpaoli, 1996). Eigenvalues (magnitude) and eigenvectors (direction) were determined for each voxel, and the intervoxel coherence maps were constructed using the average of the angle between the eigenvector of the largest eigenvalue of a given voxel and its neighbors, which represents the extent to which the vectors point in the same direction and are, therefore, coherent (Pierpaoli and Basser, 1996). Coregistration of the 2D intervoxel coherence maps to the 3D structural images was manually performed using the scanner’s slice position parameters of the SE-EPI measurements and the T1-weighted anatomical measure-
Fig. 1. Representative axial slice in Talairach space of one subject (left), its segmented white matter map (middle), and the largest possible white matter mask including all white matter maps of all subjects (right). To evaluate statistical differences between intervoxel coherence values of patients with schizophrenia and the control group, 3D segmented white matter maps were used to construct the largest possible white matter mask.
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Table 1 Clusters with reduced connectivitya Hb
Anatomical region
Sup. transv. frontopol. reg. near BA 10 Medial frontal region near BA 10 Superior temporal region near BA 42 Ant. transv. temp. reg. near BA 22 Ant. part ext. capsule Anterior superior longitudinal fascicle Anterior occipito-frontal fascicle Inf. transv. frontopol region near BA 10 Posterior cingulate near BA 23 Anterior crus internal capsule Posterior radiation corpus callosum
r r r r r r r l l l l
Mean Talairach coordinates x
y
z
Cluster size
16 18 59 49 26 32 20 13 10 14 28
52 39 26 35 4 11 10 55 55 6 50
11 12 15 19 15 21 24 3 7 10 21
398 19 6 52 12 7 7 7 9 108 7
Patients
0.25 0.32 0.14 0.17 0.31 0.19 0.27 0.27 0.24 0.29 0.20
IC
c
Controls IC
T T T T T T T T T T T
0.06 0.07 0.04 0.04 0.08 0.06 0.09 0.10 0.08 0.09 0.05
P values
Shapiro – Wilk test for residuals
0.008 0.012 0.017 0.015 0.012 0.016 0.016 0.015 0.014 0.011 0.017
0.766 0.821 0.551 0.786 0.722 0.231 0.501 0.622 0.062 0.334 0.088
c
0.41 0.44 0.23 0.27 0.41 0.29 0.38 0.43 0.41 0.44 0.27
T T T T T T T T T T T
0.08 0.10 0.09 0.08 0.07 0.09 0.08 0.15 0.17 0.09 0.05
a Clusters with significant reduced Intervoxel Coherence (IC) values for patients with schizophrenia compared with healthy controls (significance level P < 0.02). b H = Hemisphere, r = right, l = left. c IC = Mean T SD of intervoxel coherence of all voxels in these clusters.
ments. Finally, the anatomical and intervoxel coherence data sets were transformed into the normalized Talairach space (Talairach and Tournoux, 1988). During this coregistration, the voxel dimension of the intervoxel coherence maps was interpolated to 1.0 mm 1.0 mm 1.0 mm. Visual inspection of all maps for each subject suggested no need for additional susceptibility artefact correction. MRI/DTI analysis and statistics Automatic segmentation of the 3D anatomical images (MPRAGE) for each subject yielded individual probability maps ( P < 0.01) for grey and white matter (BrainVoyager 4.9; Brain Innovation, Maastricht, Netherlands). The individual 3D white matter maps were used to compute the largest possible mask (3D white matter template) (Fig. 1). To compute the difference of intervoxel coherence (IC) values between the control group and the group of patients with schizophrenia, independent t test was computed for each voxel within the 3D white matter template. The Levene’s test to check the homogeneity of variances suggested that variances can be assumed equal (Levene’s test, P = 0.409). To identify the most involved regions, clusters were defined as 6 or more neighboring voxels (6 mm3) exceeding the t test value of 2.5 ( P < 0.02). For each cluster, IC values were averaged and tabulated, and Talairach coordinates (Talairach and Tournoux, 1988) of the centers of gravity were noted (Tables 1 and 2). Clusters were assigned to the underlying white matter using 3D anatomical data. BrainVoyager and in-house software were used to
perform data analysis and visualization. To determine whether volumetric sizes may be related to differences in connectivity, the total volume of white matter for each subject was determined separately for the left and right hemispheres, thus enabling the creation of two factors—group and hemisphere—for a two-way analysis of variance (ANOVA) of white matter volume. To determine whether the size of each individual partial volume, defined as the fraction of cluster volume, and the total volume within the white matter for each subject and for each cluster, may be related to differences in connectivity, an additional ANOVA was conducted with the factors group and partial volume.
Results Group comparisons of intervoxel coherence (IC) values between patients with schizophrenia and the control group revealed statistical differences in 14 white matter clusters ( P < 0.02) (Fig. 2). No significant difference in white matter volume was found between the groups ( P > 0.8) or the hemispheres ( P > 0.9). No significant partial volume effect was found ( P > 0.9). In patients with schizophrenia, 3 clusters yielded higher IC values and 11 clusters yielded lower IC values than the same clusters in the control group (Tables 1 and 2). Of the 5 significant clusters in the left hemisphere, 1 showed an increased IC in patients with schizophrenia compared with the control group. Of the 9 significant clusters in the right hemisphere, 2 showed increased IC values for the patients (Fig. 3).
Table 2 Clusters with augmented connectivitya Anatomical region
Anterior thalamic peduncle Optic radiation Posterior part external capsule
Hb
r r l
Controls
y
z
Cluster size
Patients
x
Mean Talairach coordinates
ICc
ICc
5 25 29
8 65 19
0 6 17
7 22 150
0.32 T 0.13 0.36 T 0.09 0.49 T 0.07
0.20 T 0.06 0.25 T 0.07 0.35 T 0.09
P value
Shapiro – Wilk test for residuals
0.013 0.012 0.010
0.108 0.556 0.618
a Clusters with significant augmented Intervoxel Coherence (IC) values for patients with schizophrenia compared with healthy controls (significance level P < 0.02). b H = Hemisphere, r = right, l = left. c IC = Mean T SD of intervoxel coherence of all voxels in these clusters.
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Fig. 2. Axial slices of a representative subject showing the locations of statistically significant differences in intervoxel coherence (IC) values between patients with schizophrenia and the control group. To point out the clusters, we have chosen the significance level at P < 0.05. Numbers below each slice indicate the zcoordinate in Talairach space. Red indicates clusters of voxels with lower IC values in patients with schizophrenia (S). Purple indicates clusters of voxels with lower intervoxel coherence values in the controls (C).
In the right hemisphere, the patients with schizophrenia had lower IC values in the superior transversal frontopolar and medial frontal region near Brodman area (BA) 10, the superior temporal region near BA 22 and the anterior transversal temporal region near BA 42, the anterior part of the external capsule, the anterior part of the superior longitudinal fascicle, and the anterior part of the occipitofrontal fascicle (Table 1). Patients with schizophrenia had higher IC values than the control group in the anterior thalamic peduncle where it branches off from the internal capsule and the optic radiation (Table 2). In the left hemisphere, patients had lower IC values than the control group in the inferior transversal frontopolar region near BA 10, the posterior cingulate near BA 23, the anterior crus of the internal capsule, and the posterior radiation of the corpus callosum (Table 1). Patients with schizophrenia also registered higher IC values than the control group in the posterior part of the external capsule (Table 2). The analysis of the residuals suggests that within all clusters, the assumption regarding Gaussianity of residuals is valid. The P
values of the Shapiro – Wilk test are listed on Tables 1 and 2 for each cluster.
Discussion In the present study, we used voxel-based analysis to explore white matter connectivity in 12 patients with first episode schizophrenia. The intervoxel anisotropy parameter (IC) used in this study gives a measure for the degree of collinearity between the diffusion tensor in the reference voxel and the adjacent voxels, thus depicting connectivity more consistently than FA. Furthermore, IC guarantees a very robust signal-to-noise ratio (Pierpaoli and Basser, 1996). The analysis revealed both increased and decreased IC values in circumscribed white matter bundles. The underlying assumption that the IC data are normally distributed was confirmed by the Shapiro – Wilk test (Jones et al., 2005). All patients with first episode schizophrenia were pair-matched with a control group member according to gender and age (T6 months).
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Fig. 3. Scatter-plot of mean intervoxel coherence (IC) values (TSD) of the 14 significant clusters for patients with schizophrenia (x-axis) and subjects in the control group ( y-axis). Left-hemispheric clusters = red diamonds; right-hemispheric clusters = blue diamonds; increased IC values in patients with schizophrenia as compared with control group = dark-colored diamonds; reduced IC values in patients = light-colored diamonds.
Previously, hippocampal and white matter of splenium and genu of corpus callosum of patients with first episode schizophrenia were compared with that of healthy subjects using a region-of-interest method, but the investigations revealed no differences in FA values between the control group and the patients (Begre et al., 2003; Price et al., 2005). Other DTI studies, restricted to patients with chronic schizophrenia, have indicated alterations in white matter connectivity (Agartz et al., 2001; Ardekani et al., 2003; Buchsbaum et al., 1998; Burns et al., 2003; Foong et al., 2000; Hoptman et al., 2002; Hubl et al., 2004; Kubicki et al., 2002, 2003; Kumra et al., 2004; Lim et al., 1999; Minami et al., 2003; Okugawa et al., 2004; Sun et al., 2003; Wang et al., 2004; Wolkin et al., 2003). These studies revealed reduced relative diffusion anisotropy in the prefrontal white matter of patients with chronic schizophrenia as compared with healthy control groups (Buchsbaum et al., 1998; Hubl et al., 2004), as well as reduced FA in the frontal and occipital regions (Ardekani et al., 2003; Lim et al., 1999; Sun et al., 2003; Kumra et al., 2004), in the splenium (Agartz et al., 2001; Foong et al., 2000; Kumra et al., 2004; Kubicki et al., 2005), truncus (Kubicki et al., 2005), and the genu of the corpus callosum (Kumra et al., 2004), and bilaterally in the adjacent regions in the occipital white matter (Agartz et al., 2001) in the right hemisphere in male patients (Hoptman et al., 2002); bilaterally in the frontal, temporal, parietal, and occipital white matter (Minami et al., 2003; Kubicki et al., 2005); in the uncinate fasciculus, the anterior cingulum, and the arcuate fasciculus (Burns et al., 2003; Kubicki et al., 2002, 2005); bilaterally in the internal capsule (Kubicki et al., 2005); and in the middle cerebellar peduncles (Okugawa et al., 2004). Kubicki et al. found among the patients a lack of normal left-greater-than-right asymmetry in the uncinate fasciculus and arcuate fasciculus
(Kubicki et al., 2002). Kalus et al. (2005a,b) found reduced relative diffusion anisotropy in nondefined white matter regions of chronic schizophrenia patients compared to healthy controls, such as the amygdala and the entorhinal region. However, because of different methodological approaches, the above results are not conclusive with regard to the role of altered connectivity in the occurrence of schizophrenic symptoms. For example, several studies did not involve tissue segmentation (Begre et al., 2003; Buchsbaum et al., 1998; Foong et al., 2000; Kalus et al., 2005a,b; Kubicki et al., 2002; Kumra et al., 2004; Minami et al., 2003; Okugawa et al., 2004; Price et al., 2005; Wang et al., 2003), direct matching of subjects (Agartz et al., 2001; Buchsbaum et al., 1998; Foong et al., 2002; Kalus et al., 2005a,b; Kubicki et al., 2003, 2005; Kumra et al., 2004; Minami et al., 2003; Okugawa et al., 2004; Price et al., 2005; Wang et al., 2003), or more than a few slices (Buchsbaum et al., 1998; Minami et al., 2003). Age-related loss of FA in white matter, as measured by DTI, was reported and may accelerate in old age (Sullivan and Pfefferbaum, 2003; Nusbaum et al., 2001; Pfefferbaum and Sullivan, 2003). The present study takes white matter aging into account by matching 24 subjects by gender and age (T6 months) to create 12 pairs for close comparison. Some researchers have used a voxel-based analysis of their DTI data (Agartz et al., 2001; Ardekani et al., 2003; Buchsbaum et al., 1998; Burns et al., 2003; Foong et al., 2002, Kubicki et al., 2005), whereas others have used a region-of-interest method (Begre et al., 2003; Foong et al., 2000; Kalus et al., 2005a,b; Kubicki et al., 2002, 2003; Minami et al., 2003; Okugawa et al., 2005; Price et al., 2005; Wang et al., 2003). While the first method represents an exploratory approach, the latter is a hypothesis-driven approach. Because we focused on general white matter changes in the brain, we employed
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a voxel-based method. We found 14 clusters containing more than 6 neighboring voxels with significant differences in IC values ( P < 0.02) between healthy subjects and patients with schizophrenia. Our results confirm previous studies demonstrating reduced anisotropy values in the frontal, temporal, parietal, and occipital lobes, corpus callosum, and left internal capsule of patients with schizophrenia compared with control groups. In addition, we found reduced IC in the left posterior cingulate. The intervoxel anisotropy parameter (IC) used in this study provides a measure of the degree of collinearity between the diffusion tensor in the reference voxel and the adjacent voxels. A recent DTI study suggested that high IC value indicates both the local strength of FA and the agreement of fiber direction in neighboring voxels (Deutsch et al., 2005). The same authors used IC values, as previously investigated the anatomical differences between controls and reading impaired adults (Klingberg et al., 2000). In this study, both FA and IC were compared. They found reliable differences in FA in the temporoparietal region bilaterally but more extreme differences in the left hemisphere. Furthermore, FA values in the left temporoparietal lobe correlated with reading performance in both poor and normal readers. Although group differences in IC were not observed, quantification of the fiber direction revealed that a slight preponderance of axons in the left temporoparietal region were oriented in an anterior – posterior direction. They suggested that axons in this area are important for efficient connectivity between temporoparietal and frontal regions and thus may be important for reading. This finding suggests that IC is a measure of the underlying direction of fragments of fibers and also of longer fiber segments. Most of the cortical efferents project via the internal capsule. Projections to the basal ganglia travel via the external capsule (Stewards, 2000). For example, in BA 10 in the left and right frontal superior regions and in the anterior crus of the left internal capsule, we found reduced IC values among patients with schizophrenia as compared with control groups. BA 10 is related to higher order function, in which corticothalamal fiber tracts connect to the dorsomedian thalamic nucleus, later crossing the anterior crus of the internal capsule and leading to the three other cerebral lobes and the hypothalamus. Furthermore, we found white matter changes in the right temporal superior region near the auditory integration area BA 42 and the right auditory association area BA 22, a finding perhaps related to auditory hallucinations in our patients. In studies using functional MRI, several researchers (Dierks et al., 1999; Shergill et al., 2003) have described a relationship between these areas and auditory hallucinations, and the DTI results of Hubl et al. confirm their findings (Hubl et al., 2004). Schizophrenia is not a well-defined disease; rather, it is diagnosed from a constellation of clinical symptoms that include affective, motor, and cognitive behaviors. Often, more than one system is affected. We found reduced IC in the right superior longitudinal fascicle, comprising numerous connections between the frontal lobe, the occipital lobe, and the posterior part of the temporal lobe. It seems evident that this disconnectivity may cause some clinically relevant disturbances. Yet, the changes we found in numerous white matter bundles—results that confirm previous findings—could partially explain the heterogeneous symptoms of schizophrenia. Further studies are needed to correlate structural alterations with neurophysiological and clinical symptoms. Our finding of regions with higher IC values in patients with schizophrenia than in the control group (Table 1) was unexpected, since nearly all previous studies in patients with schizophrenia
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reported either similar or reduced FA values in white matter regions as compared with control groups. In a previous study of hallucinating patients with chronic schizophrenia, higher FA values were found in the lateral left and right temporoparietal section of the arcuate fasciculus, close to the auditory regions and the posterior end of the Sylvian fissure, whereas healthy subjects had higher FA values in the medial parts of the arcuate fasciculus (Hubl et al., 2004). The neurobiological functional correlate of an increase in IC in our patients with first episode schizophrenia as compared with the control group is not clear. Most in vivo human and animal studies of DTI during neuronal development and functional disturbances in neuropsychiatric diseases suggest that an increase in anisotropy is related to increased connectivity in white matter bundles (Dong and Greenough, 2004). In general, this may facilitate dysfunctional coactivation of sensory areas, as has been described previously for auditory areas, during auditory hallucinations in patients with chronic schizophrenia (Dierks et al., 1999; Shergill et al., 2000). In the present study, more altered voxels were found in the right hemisphere (9 clusters with 530 voxels) than in the left hemisphere (5 clusters with 281 voxels). Only one significant voxel cluster (150 voxels) in which IC values were higher in patients than in healthy subjects was found in the left hemisphere, compared with 2 clusters comprising 29 voxels in the right hemisphere. Significant voxel clusters in which IC values were lower in patients than in healthy subjects were more concentrated in the right hemisphere (a total of 7 clusters comprising 501 voxels, compared with 4 clusters comprising 131 voxels in the left hemisphere). Given that neither a group effect nor a left-versus-right hemispheric effect was found in the white matter volumes, these results indicate an excess of white matter connectivity in the left hemisphere or a lack of it in the right hemisphere in patients with schizophrenia. Several authors have argued that there is a lack of cerebral lateralization in schizophrenia (Crow, 1999; Strik et al., 1994). Others also suggest a right-sided brain pathology in schizophrenia (Holinger et al., 1999; Matsumoto et al., 2001). Furthermore, Matsumoto found an inverse relation of abnormalities in the right superior temporal gyrus to the severity of hallucinations and thought disorders (Matsumoto et al., 2001). The significance of the asymmetries existing in our first episode sample is not clear. The asymmetries could be part of structural and functional neurodevelopmentally based differences between the two hemispheres in certain regions. Also, in healthy subjects, some evidence supports gradual maturation of certain white matter pathways during childhood and adolescence (Paus et al., 1999). Thus, maturation of white matter bundles may be different in patients with schizophrenia than in healthy subjects. In addition, we generally found smaller cluster sizes as compared with previous studies in patients with chronic schizophrenia. This may stem from a different methodological approach to data acquisition (i.e., different magnetic resonance systems, different acquisition modes) and data analysis (using IC instead of most commonly used FA), or it may reflect the beginning of a deleterious disease process in our sample of patients with first episode schizophrenia. However, the manifestation of an atypical, asymmetric right – left distribution of IC in patients, as compared with the control group, shows deviations in the integrity of the associating long fiber tracts—that is, those connecting the frontal lobe (area 10) with the mediodorsal nucleus of the thalamus and the basal ganglia. Globally, this means an altered fronto-thalamo-cerebellar circuit, mentioned by Andreasen et al. as the structural core of schizophrenic symptoms (Andreasen et al., 1998). Based on these significant differences in
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long association bundles in the medullary part of the brains of patients and healthy subjects, we can postulate a genetic—or at least an early—defect in white matter development as previously suggested (Hakak et al., 2001; Tkachev et al., 2003). It should be mentioned that the locations of differences between schizophrenic patients and controls are subject to great variation, depending on the size of the applied Gaussian smoothing kernel (Jones et al., 2005). In fact, Jones et al. demonstrated that different conclusions regarding apparent patient versus control differences are possible within the same dataset, depending on the size of the smoothing filter used for voxel-based analysis of DTI data (Jones et al., 2005). Moreover, the same authors stressed the point that nonnormality of the DTI data may additionally degrade conclusions on group differences within white matter. In our study, we observed that the data follow a normal distribution in both, regions with increased and reduced IC values for schizophrenic patients as compared to controls. This finding was also reported in part in previous studies. Therefore, it is unlikely that our results are biased by the filter size we used. Lastly, a DTI study investigating water diffusion changes in Wallerian degeneration showed that secondary white matter degeneration was accompanied by a large reduction in diffusion anisotropy only in regions where fibers are arranged in isolated bundles of parallel fibers. In regions where the degenerated pathway crosses other tracts paradoxically, there was almost no change in diffusion anisotropy but a significant change in the measured orientation of fibers (Pierpaoli et al., 2001). Accordingly, our results could be attributed to fiber bundle that crosses the measured area. However, in our study, the voxel dimension we measured was 3.75 mm 3.75 mm 5 mm, a dimension far too large to account for crossing or branching of fibers within a voxel. In contrast to most previous studies, we found not just regions of the brain with reduced anisotropy but also specific regions with higher anisotropy in patients with schizophrenia, as compared with the control group. Furthermore, we found a right – left asymmetry. Finally, aside from the fact that in the present study, the sample size was small, which could also introduce false positive results, our preliminary findings provide strong evidence for compromised white matter connectivity in several brain regions early in the schizophrenic disease process, which probably explains the heterogeneous symptoms of this enigmatic disease.
Acknowledgments We gratefully acknowledge the Swiss National Science Foundation for funding support (3200-059077.99 to Dr. Dierks). Further thanks are due to Regula Schweizer for performing the magnetic resonance imaging measurements and Mrs. Baechler for proofreading the manuscript. References Agartz, I., Andersson, J.L., Skare, S., 2001. Abnormal brain white matter in schizophrenia: a diffusion tensor imaging study. NeuroReport 12, 2251 – 2254. Andreasen, N.C., Paradiso, S., O’Leary, D.S., 1998. ‘‘Cognitive dysmetria’’ as an integrative theory of schizophrenia: a dysfunction in cortical – subcortical – cerebellar circuitry? Schizophr. Bull. 24, 203 – 218. Ardekani, B.A., Nierenberg, J., Hoptman, M.J., Javitt, D.C., Lim, K.O., 2003. MRI study of white matter diffusion anisotropy in schizophrenia. NeuroReport 14, 2025 – 2029.
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Alterations of white matter connectivity in first episode schizophrenia Andrea Federspiel,a,1 Stefan Begre´,b,*,1 Claus Kiefer,a,c Gerhard Schroth,c Werner K. Strik,a and Thomas Dierksa a
University Hospital of Clinical Psychiatry, Department of Psychiatric Neurophysiology, Berne, Switzerland Department of General Internal Medicine, Division of Psychosomatic Medicine, Inselspital Bern, University of Berne, CH-3010 Berne, Switzerland c Inselspital Berne, Department of Neuroradiology, University of Berne, Berne, Switzerland b
Received 22 August 2005; revised 12 December 2005; accepted 22 January 2006 Available online 19 April 2006
Cerebral disconnectivity due to white matter alterations in patients with chronic schizophrenia assessed by diffusion tensor imaging has been reported previously. The aim of this preliminary study is to investigate whether cerebral disconnectivity can be detected as early as the first episode of schizophrenia. Intervoxel coherence values were compared by voxel-based t test in 12 patients with first episode schizophrenia and 12 age- and gender-matched control groups. We detected 14 circumscribed significant clusters ( P < 0.02), 3 of them with higher, and 11 of them with lower IC values for patients with schizophrenia than for healthy control groups. We interpret these white matter alterations in different regions to be disconnected fiber tracts already present early in schizophrenic disease progression. D 2006 Elsevier Inc. All rights reserved. Keywords: Intervoxel coherence; Fractional anisotropy; Diffusion tensor imaging; Gray matter; White matter; First episode schizophrenia
Introduction Schizophrenia has been described as a disorder of disrupted connectivity in the fronto-thalamo-striato-cerebellar circuit (Andreasen et al., 1998). The basis of impaired connectivity may be subtle gray and white matter lesions, as described by several investigators (Shenton et al., 2001). Diffusion tensor imaging (DTI) is a relatively new approach to assessing tissue structure and geometry at a microscopic level. It measures diffusion-driven displacements of molecules during their random path along axonal fibers, expressed as fractional anisotropy (FA) or intervoxel coherence (IC) ranging from 0 (isotropic medium) to 1 (fully anisotropic medium). IC guarantees a very robust signal-to-noise ratio and considers the degree of collinearity between the diffusion
* Corresponding author. Fax: +41 31 382 11 84. E-mail address: [email protected] (S. Begre´). 1 These authors contributed equally to this work. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ - see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2006.01.015
tensor of the reference voxel and the adjacent voxels (Pierpaoli and Basser, 1996; Pfefferbaum et al., 2000); in literature, IC is also labeled as Coherence Index (Deutsch et al., 2005). IC is a measure similar to FA (Klingberg et al., 1999, 2000). It is related to FA value; high IC value indicates both the local strength of FA and the agreement of fiber direction in neighboring voxels (Deutsch et al., 2005). In both studies, the main orientation of major fiber tracts important for reading and spelling were reported using FA and IC measures. Previous studies have shown a reduced FA in schizophrenia (Agartz et al., 2001; Ardekani et al., 2003; Buchsbaum et al., 1998; Burns et al., 2003; Foong et al., 2000; Hubl et al., 2004; Kubicki et al., 2003, 2005; Kumra et al., 2004; Lim et al., 1999; Minami et al., 2003; Okugawa et al., 2004; Sun et al., 2003; Wang et al., 2004). Only one study reported augmented FA in circumscribed tracts of the brain in hallucinating, chronic schizophrenic patients as compared with FA in healthy control groups (Hubl et al., 2004). Using FA in first episode schizophrenia, two studies found no differences compared to healthy controls in the hippocampus (Begre et al., 2003) or the splenium and genu of corpus callosum (Price et al., 2005). Using IC, two studies of the same group compared amygdale and entorhinal regions in chronic schizophrenia patients to healthy controls (Kalus et al., 2005a,b). To our knowledge, IC has never been used to investigate white matter in first episode schizophrenic patients. Several studies suggest that schizophrenia is a progressive disease accompanied by loss of gray and white matter volume (Cahn et al., 2002; Gogtay et al., 2004; Velakoulis et al., 2002). However, it is not clear whether changes in white matter structure exist from childhood, prior to the first psychotic symptoms, or develop during disease progression. To investigate whether previously described anisotropy changes of white matter in chronic schizophrenia are present at the beginning of the schizophrenic course, we measured IC as an indication of connectivity in 12 first episode psychosis patients. We used 12 ageand gender-matched subjects as the control group. From previous results of studies in chronic schizophrenia using FA, we expected to find clusters of reduced IC in corpus callosum, cingulum, main white matter fascicles, as well as in frontal, temporal, and occipital white matter regions.
A. Federspiel et al. / Neurobiology of Disease 22 (2006) 702 – 709
Materials and methods
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of view [FOV] = 256 mm, voxel dimension = 1.0 mm 1.0 mm 1.0 mm).
Subjects DTI recording and processing Twelve patients (8 men and 4 women, mean age 23.4 years T 3.0 years SD, range 18.1 – 28.7 years, all right-handed) hospitalized with their first episode of schizophrenia, diagnosed according to ICD-10 diagnosis criteria (Bramer, 1988) were pair matched by gender and age (T6 months) with 12 healthy volunteers (mean age of 23.2 years T 3.1 years SD, range 17.6 – 28.5 years, all righthanded). Patients with schizophrenia were recruited from the first episode ward of the University Hospital of Clinical Psychiatry in Berne; the control group consisted of normal volunteers from the region. Patients and their relatives were questioned about the development of psychotic symptoms, substance abuse, and any other psychiatric or medical conditions. All patients had at least first-rank symptoms, but one lacked auditory hallucinations. Three patients, including the one without auditory hallucinations, reported sporadic cannabis use. At the time of the measurements, the average duration of illness was 115.7 days (SD T 91.0 days, range 14 – 270 days), and the average duration of medication was 10.5 days (SD T 11.0 days, range 0 – 35 days). Three patients were medicated with risperidone, 3 with olanzapine, 2 with quetiapine, 1 with amisulpride, and 2 with both haloperidol and risperidone. One patient was not medicated. None of the control subjects had a history of major medical or neurological disorders, substance abuse, or other psychiatric diseases, or received psychotropic medication before hospitalization. All subjects gave written informed consent, and the study received approval from the local ethical committee. For measurements in the magnetic resonance imaging (MRI) scanner, subjects received no specific instructions other than to relax and keep their head still. The use of restraining foam pads minimized head motion. MRI recording MRI imaging was performed on a 1.5-T standard clinical MRI scanner (Siemens Vision, Erlangen, Germany), using the standard radio-frequency head coil. First, a high-resolution three-dimensional data set covering the whole brain was collected for each subject through a 3D magnetization-prepared rapid-acquisition gradient echo (MP-RAGE) sequence. In all, 192 scans were accumulated (TR = 6 s, TE = 95 ms, matrix size = 256 256 voxels, field
For diffusion-weighted imaging, a single-shot spin-echo – echoplanar imaging (SE-EPI) sequence was acquired in the same session. Gradient amplitudes and duration were chosen so as to enable detection of tissue-dependent diffusion coefficients by the signal attenuation: G = 22 mT/m, duration TE = 20 ms, intergradient time interval = 40.00 ms, TR = 3000 ms. In total, 12 axial continuous slices (5 mm slice thickness, no gap) were acquired. The matrix size = 64 64 voxels, field of view [FOV] = 240 mm, voxel dimension = 3.75 mm 3.75 mm 5.0 mm. The diffusion sensitizing gradients were applied simultaneously on two axes around the 180- pulse at b = 1800 s/mm2/axis along 6 noncollinear directions: ( G x , G y, G z ) =pffiffi[(1, 0, 1), (1, 0, 1), ffi (0, 1, 1), (0, 1, 1), (1, 1, 0), (1, 1, 0)]/ 2. This gradient scheme was chosen to minimize acquisition time, so as to include as many schizophrenic patients as possible in the study. This, despite suggestions that the optimal gradient scheme may include more than 6 gradient directions (Jones, 2004; Jones et al., 1999). Additionally, one image was acquired with no gradients applied. Eddy-current corrections were included. Images were smoothed using a Gaussian filter with a FWHM of 7.5 mm. To test for nonnormality of the residuals, the Shapiro – Wilk test was computed for each voxel of each cluster. With the Shapiro – Wilk test, the null hypothesis is that residuals follow an normal distribution, i.e., if the P value is greater than alpha value of 0.05, then the null hypothesis will not be rejected (Jones et al., 2005). The calculation and diagonalization of the diffusion tensor were based on the multivariate regression approach (Basser et al., 1994). Six independent elements of the diffusion tensor were extracted (Basser and Pierpaoli, 1996). Eigenvalues (magnitude) and eigenvectors (direction) were determined for each voxel, and the intervoxel coherence maps were constructed using the average of the angle between the eigenvector of the largest eigenvalue of a given voxel and its neighbors, which represents the extent to which the vectors point in the same direction and are, therefore, coherent (Pierpaoli and Basser, 1996). Coregistration of the 2D intervoxel coherence maps to the 3D structural images was manually performed using the scanner’s slice position parameters of the SE-EPI measurements and the T1-weighted anatomical measure-
Fig. 1. Representative axial slice in Talairach space of one subject (left), its segmented white matter map (middle), and the largest possible white matter mask including all white matter maps of all subjects (right). To evaluate statistical differences between intervoxel coherence values of patients with schizophrenia and the control group, 3D segmented white matter maps were used to construct the largest possible white matter mask.
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Table 1 Clusters with reduced connectivitya Hb
Anatomical region
Sup. transv. frontopol. reg. near BA 10 Medial frontal region near BA 10 Superior temporal region near BA 42 Ant. transv. temp. reg. near BA 22 Ant. part ext. capsule Anterior superior longitudinal fascicle Anterior occipito-frontal fascicle Inf. transv. frontopol region near BA 10 Posterior cingulate near BA 23 Anterior crus internal capsule Posterior radiation corpus callosum
r r r r r r r l l l l
Mean Talairach coordinates x
y
z
Cluster size
16 18 59 49 26 32 20 13 10 14 28
52 39 26 35 4 11 10 55 55 6 50
11 12 15 19 15 21 24 3 7 10 21
398 19 6 52 12 7 7 7 9 108 7
Patients
0.25 0.32 0.14 0.17 0.31 0.19 0.27 0.27 0.24 0.29 0.20
IC
c
Controls IC
T T T T T T T T T T T
0.06 0.07 0.04 0.04 0.08 0.06 0.09 0.10 0.08 0.09 0.05
P values
Shapiro – Wilk test for residuals
0.008 0.012 0.017 0.015 0.012 0.016 0.016 0.015 0.014 0.011 0.017
0.766 0.821 0.551 0.786 0.722 0.231 0.501 0.622 0.062 0.334 0.088
c
0.41 0.44 0.23 0.27 0.41 0.29 0.38 0.43 0.41 0.44 0.27
T T T T T T T T T T T
0.08 0.10 0.09 0.08 0.07 0.09 0.08 0.15 0.17 0.09 0.05
a Clusters with significant reduced Intervoxel Coherence (IC) values for patients with schizophrenia compared with healthy controls (significance level P < 0.02). b H = Hemisphere, r = right, l = left. c IC = Mean T SD of intervoxel coherence of all voxels in these clusters.
ments. Finally, the anatomical and intervoxel coherence data sets were transformed into the normalized Talairach space (Talairach and Tournoux, 1988). During this coregistration, the voxel dimension of the intervoxel coherence maps was interpolated to 1.0 mm 1.0 mm 1.0 mm. Visual inspection of all maps for each subject suggested no need for additional susceptibility artefact correction. MRI/DTI analysis and statistics Automatic segmentation of the 3D anatomical images (MPRAGE) for each subject yielded individual probability maps ( P < 0.01) for grey and white matter (BrainVoyager 4.9; Brain Innovation, Maastricht, Netherlands). The individual 3D white matter maps were used to compute the largest possible mask (3D white matter template) (Fig. 1). To compute the difference of intervoxel coherence (IC) values between the control group and the group of patients with schizophrenia, independent t test was computed for each voxel within the 3D white matter template. The Levene’s test to check the homogeneity of variances suggested that variances can be assumed equal (Levene’s test, P = 0.409). To identify the most involved regions, clusters were defined as 6 or more neighboring voxels (6 mm3) exceeding the t test value of 2.5 ( P < 0.02). For each cluster, IC values were averaged and tabulated, and Talairach coordinates (Talairach and Tournoux, 1988) of the centers of gravity were noted (Tables 1 and 2). Clusters were assigned to the underlying white matter using 3D anatomical data. BrainVoyager and in-house software were used to
perform data analysis and visualization. To determine whether volumetric sizes may be related to differences in connectivity, the total volume of white matter for each subject was determined separately for the left and right hemispheres, thus enabling the creation of two factors—group and hemisphere—for a two-way analysis of variance (ANOVA) of white matter volume. To determine whether the size of each individual partial volume, defined as the fraction of cluster volume, and the total volume within the white matter for each subject and for each cluster, may be related to differences in connectivity, an additional ANOVA was conducted with the factors group and partial volume.
Results Group comparisons of intervoxel coherence (IC) values between patients with schizophrenia and the control group revealed statistical differences in 14 white matter clusters ( P < 0.02) (Fig. 2). No significant difference in white matter volume was found between the groups ( P > 0.8) or the hemispheres ( P > 0.9). No significant partial volume effect was found ( P > 0.9). In patients with schizophrenia, 3 clusters yielded higher IC values and 11 clusters yielded lower IC values than the same clusters in the control group (Tables 1 and 2). Of the 5 significant clusters in the left hemisphere, 1 showed an increased IC in patients with schizophrenia compared with the control group. Of the 9 significant clusters in the right hemisphere, 2 showed increased IC values for the patients (Fig. 3).
Table 2 Clusters with augmented connectivitya Anatomical region
Anterior thalamic peduncle Optic radiation Posterior part external capsule
Hb
r r l
Controls
y
z
Cluster size
Patients
x
Mean Talairach coordinates
ICc
ICc
5 25 29
8 65 19
0 6 17
7 22 150
0.32 T 0.13 0.36 T 0.09 0.49 T 0.07
0.20 T 0.06 0.25 T 0.07 0.35 T 0.09
P value
Shapiro – Wilk test for residuals
0.013 0.012 0.010
0.108 0.556 0.618
a Clusters with significant augmented Intervoxel Coherence (IC) values for patients with schizophrenia compared with healthy controls (significance level P < 0.02). b H = Hemisphere, r = right, l = left. c IC = Mean T SD of intervoxel coherence of all voxels in these clusters.
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Fig. 2. Axial slices of a representative subject showing the locations of statistically significant differences in intervoxel coherence (IC) values between patients with schizophrenia and the control group. To point out the clusters, we have chosen the significance level at P < 0.05. Numbers below each slice indicate the zcoordinate in Talairach space. Red indicates clusters of voxels with lower IC values in patients with schizophrenia (S). Purple indicates clusters of voxels with lower intervoxel coherence values in the controls (C).
In the right hemisphere, the patients with schizophrenia had lower IC values in the superior transversal frontopolar and medial frontal region near Brodman area (BA) 10, the superior temporal region near BA 22 and the anterior transversal temporal region near BA 42, the anterior part of the external capsule, the anterior part of the superior longitudinal fascicle, and the anterior part of the occipitofrontal fascicle (Table 1). Patients with schizophrenia had higher IC values than the control group in the anterior thalamic peduncle where it branches off from the internal capsule and the optic radiation (Table 2). In the left hemisphere, patients had lower IC values than the control group in the inferior transversal frontopolar region near BA 10, the posterior cingulate near BA 23, the anterior crus of the internal capsule, and the posterior radiation of the corpus callosum (Table 1). Patients with schizophrenia also registered higher IC values than the control group in the posterior part of the external capsule (Table 2). The analysis of the residuals suggests that within all clusters, the assumption regarding Gaussianity of residuals is valid. The P
values of the Shapiro – Wilk test are listed on Tables 1 and 2 for each cluster.
Discussion In the present study, we used voxel-based analysis to explore white matter connectivity in 12 patients with first episode schizophrenia. The intervoxel anisotropy parameter (IC) used in this study gives a measure for the degree of collinearity between the diffusion tensor in the reference voxel and the adjacent voxels, thus depicting connectivity more consistently than FA. Furthermore, IC guarantees a very robust signal-to-noise ratio (Pierpaoli and Basser, 1996). The analysis revealed both increased and decreased IC values in circumscribed white matter bundles. The underlying assumption that the IC data are normally distributed was confirmed by the Shapiro – Wilk test (Jones et al., 2005). All patients with first episode schizophrenia were pair-matched with a control group member according to gender and age (T6 months).
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Fig. 3. Scatter-plot of mean intervoxel coherence (IC) values (TSD) of the 14 significant clusters for patients with schizophrenia (x-axis) and subjects in the control group ( y-axis). Left-hemispheric clusters = red diamonds; right-hemispheric clusters = blue diamonds; increased IC values in patients with schizophrenia as compared with control group = dark-colored diamonds; reduced IC values in patients = light-colored diamonds.
Previously, hippocampal and white matter of splenium and genu of corpus callosum of patients with first episode schizophrenia were compared with that of healthy subjects using a region-of-interest method, but the investigations revealed no differences in FA values between the control group and the patients (Begre et al., 2003; Price et al., 2005). Other DTI studies, restricted to patients with chronic schizophrenia, have indicated alterations in white matter connectivity (Agartz et al., 2001; Ardekani et al., 2003; Buchsbaum et al., 1998; Burns et al., 2003; Foong et al., 2000; Hoptman et al., 2002; Hubl et al., 2004; Kubicki et al., 2002, 2003; Kumra et al., 2004; Lim et al., 1999; Minami et al., 2003; Okugawa et al., 2004; Sun et al., 2003; Wang et al., 2004; Wolkin et al., 2003). These studies revealed reduced relative diffusion anisotropy in the prefrontal white matter of patients with chronic schizophrenia as compared with healthy control groups (Buchsbaum et al., 1998; Hubl et al., 2004), as well as reduced FA in the frontal and occipital regions (Ardekani et al., 2003; Lim et al., 1999; Sun et al., 2003; Kumra et al., 2004), in the splenium (Agartz et al., 2001; Foong et al., 2000; Kumra et al., 2004; Kubicki et al., 2005), truncus (Kubicki et al., 2005), and the genu of the corpus callosum (Kumra et al., 2004), and bilaterally in the adjacent regions in the occipital white matter (Agartz et al., 2001) in the right hemisphere in male patients (Hoptman et al., 2002); bilaterally in the frontal, temporal, parietal, and occipital white matter (Minami et al., 2003; Kubicki et al., 2005); in the uncinate fasciculus, the anterior cingulum, and the arcuate fasciculus (Burns et al., 2003; Kubicki et al., 2002, 2005); bilaterally in the internal capsule (Kubicki et al., 2005); and in the middle cerebellar peduncles (Okugawa et al., 2004). Kubicki et al. found among the patients a lack of normal left-greater-than-right asymmetry in the uncinate fasciculus and arcuate fasciculus
(Kubicki et al., 2002). Kalus et al. (2005a,b) found reduced relative diffusion anisotropy in nondefined white matter regions of chronic schizophrenia patients compared to healthy controls, such as the amygdala and the entorhinal region. However, because of different methodological approaches, the above results are not conclusive with regard to the role of altered connectivity in the occurrence of schizophrenic symptoms. For example, several studies did not involve tissue segmentation (Begre et al., 2003; Buchsbaum et al., 1998; Foong et al., 2000; Kalus et al., 2005a,b; Kubicki et al., 2002; Kumra et al., 2004; Minami et al., 2003; Okugawa et al., 2004; Price et al., 2005; Wang et al., 2003), direct matching of subjects (Agartz et al., 2001; Buchsbaum et al., 1998; Foong et al., 2002; Kalus et al., 2005a,b; Kubicki et al., 2003, 2005; Kumra et al., 2004; Minami et al., 2003; Okugawa et al., 2004; Price et al., 2005; Wang et al., 2003), or more than a few slices (Buchsbaum et al., 1998; Minami et al., 2003). Age-related loss of FA in white matter, as measured by DTI, was reported and may accelerate in old age (Sullivan and Pfefferbaum, 2003; Nusbaum et al., 2001; Pfefferbaum and Sullivan, 2003). The present study takes white matter aging into account by matching 24 subjects by gender and age (T6 months) to create 12 pairs for close comparison. Some researchers have used a voxel-based analysis of their DTI data (Agartz et al., 2001; Ardekani et al., 2003; Buchsbaum et al., 1998; Burns et al., 2003; Foong et al., 2002, Kubicki et al., 2005), whereas others have used a region-of-interest method (Begre et al., 2003; Foong et al., 2000; Kalus et al., 2005a,b; Kubicki et al., 2002, 2003; Minami et al., 2003; Okugawa et al., 2005; Price et al., 2005; Wang et al., 2003). While the first method represents an exploratory approach, the latter is a hypothesis-driven approach. Because we focused on general white matter changes in the brain, we employed
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a voxel-based method. We found 14 clusters containing more than 6 neighboring voxels with significant differences in IC values ( P < 0.02) between healthy subjects and patients with schizophrenia. Our results confirm previous studies demonstrating reduced anisotropy values in the frontal, temporal, parietal, and occipital lobes, corpus callosum, and left internal capsule of patients with schizophrenia compared with control groups. In addition, we found reduced IC in the left posterior cingulate. The intervoxel anisotropy parameter (IC) used in this study provides a measure of the degree of collinearity between the diffusion tensor in the reference voxel and the adjacent voxels. A recent DTI study suggested that high IC value indicates both the local strength of FA and the agreement of fiber direction in neighboring voxels (Deutsch et al., 2005). The same authors used IC values, as previously investigated the anatomical differences between controls and reading impaired adults (Klingberg et al., 2000). In this study, both FA and IC were compared. They found reliable differences in FA in the temporoparietal region bilaterally but more extreme differences in the left hemisphere. Furthermore, FA values in the left temporoparietal lobe correlated with reading performance in both poor and normal readers. Although group differences in IC were not observed, quantification of the fiber direction revealed that a slight preponderance of axons in the left temporoparietal region were oriented in an anterior – posterior direction. They suggested that axons in this area are important for efficient connectivity between temporoparietal and frontal regions and thus may be important for reading. This finding suggests that IC is a measure of the underlying direction of fragments of fibers and also of longer fiber segments. Most of the cortical efferents project via the internal capsule. Projections to the basal ganglia travel via the external capsule (Stewards, 2000). For example, in BA 10 in the left and right frontal superior regions and in the anterior crus of the left internal capsule, we found reduced IC values among patients with schizophrenia as compared with control groups. BA 10 is related to higher order function, in which corticothalamal fiber tracts connect to the dorsomedian thalamic nucleus, later crossing the anterior crus of the internal capsule and leading to the three other cerebral lobes and the hypothalamus. Furthermore, we found white matter changes in the right temporal superior region near the auditory integration area BA 42 and the right auditory association area BA 22, a finding perhaps related to auditory hallucinations in our patients. In studies using functional MRI, several researchers (Dierks et al., 1999; Shergill et al., 2003) have described a relationship between these areas and auditory hallucinations, and the DTI results of Hubl et al. confirm their findings (Hubl et al., 2004). Schizophrenia is not a well-defined disease; rather, it is diagnosed from a constellation of clinical symptoms that include affective, motor, and cognitive behaviors. Often, more than one system is affected. We found reduced IC in the right superior longitudinal fascicle, comprising numerous connections between the frontal lobe, the occipital lobe, and the posterior part of the temporal lobe. It seems evident that this disconnectivity may cause some clinically relevant disturbances. Yet, the changes we found in numerous white matter bundles—results that confirm previous findings—could partially explain the heterogeneous symptoms of schizophrenia. Further studies are needed to correlate structural alterations with neurophysiological and clinical symptoms. Our finding of regions with higher IC values in patients with schizophrenia than in the control group (Table 1) was unexpected, since nearly all previous studies in patients with schizophrenia
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reported either similar or reduced FA values in white matter regions as compared with control groups. In a previous study of hallucinating patients with chronic schizophrenia, higher FA values were found in the lateral left and right temporoparietal section of the arcuate fasciculus, close to the auditory regions and the posterior end of the Sylvian fissure, whereas healthy subjects had higher FA values in the medial parts of the arcuate fasciculus (Hubl et al., 2004). The neurobiological functional correlate of an increase in IC in our patients with first episode schizophrenia as compared with the control group is not clear. Most in vivo human and animal studies of DTI during neuronal development and functional disturbances in neuropsychiatric diseases suggest that an increase in anisotropy is related to increased connectivity in white matter bundles (Dong and Greenough, 2004). In general, this may facilitate dysfunctional coactivation of sensory areas, as has been described previously for auditory areas, during auditory hallucinations in patients with chronic schizophrenia (Dierks et al., 1999; Shergill et al., 2000). In the present study, more altered voxels were found in the right hemisphere (9 clusters with 530 voxels) than in the left hemisphere (5 clusters with 281 voxels). Only one significant voxel cluster (150 voxels) in which IC values were higher in patients than in healthy subjects was found in the left hemisphere, compared with 2 clusters comprising 29 voxels in the right hemisphere. Significant voxel clusters in which IC values were lower in patients than in healthy subjects were more concentrated in the right hemisphere (a total of 7 clusters comprising 501 voxels, compared with 4 clusters comprising 131 voxels in the left hemisphere). Given that neither a group effect nor a left-versus-right hemispheric effect was found in the white matter volumes, these results indicate an excess of white matter connectivity in the left hemisphere or a lack of it in the right hemisphere in patients with schizophrenia. Several authors have argued that there is a lack of cerebral lateralization in schizophrenia (Crow, 1999; Strik et al., 1994). Others also suggest a right-sided brain pathology in schizophrenia (Holinger et al., 1999; Matsumoto et al., 2001). Furthermore, Matsumoto found an inverse relation of abnormalities in the right superior temporal gyrus to the severity of hallucinations and thought disorders (Matsumoto et al., 2001). The significance of the asymmetries existing in our first episode sample is not clear. The asymmetries could be part of structural and functional neurodevelopmentally based differences between the two hemispheres in certain regions. Also, in healthy subjects, some evidence supports gradual maturation of certain white matter pathways during childhood and adolescence (Paus et al., 1999). Thus, maturation of white matter bundles may be different in patients with schizophrenia than in healthy subjects. In addition, we generally found smaller cluster sizes as compared with previous studies in patients with chronic schizophrenia. This may stem from a different methodological approach to data acquisition (i.e., different magnetic resonance systems, different acquisition modes) and data analysis (using IC instead of most commonly used FA), or it may reflect the beginning of a deleterious disease process in our sample of patients with first episode schizophrenia. However, the manifestation of an atypical, asymmetric right – left distribution of IC in patients, as compared with the control group, shows deviations in the integrity of the associating long fiber tracts—that is, those connecting the frontal lobe (area 10) with the mediodorsal nucleus of the thalamus and the basal ganglia. Globally, this means an altered fronto-thalamo-cerebellar circuit, mentioned by Andreasen et al. as the structural core of schizophrenic symptoms (Andreasen et al., 1998). Based on these significant differences in
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long association bundles in the medullary part of the brains of patients and healthy subjects, we can postulate a genetic—or at least an early—defect in white matter development as previously suggested (Hakak et al., 2001; Tkachev et al., 2003). It should be mentioned that the locations of differences between schizophrenic patients and controls are subject to great variation, depending on the size of the applied Gaussian smoothing kernel (Jones et al., 2005). In fact, Jones et al. demonstrated that different conclusions regarding apparent patient versus control differences are possible within the same dataset, depending on the size of the smoothing filter used for voxel-based analysis of DTI data (Jones et al., 2005). Moreover, the same authors stressed the point that nonnormality of the DTI data may additionally degrade conclusions on group differences within white matter. In our study, we observed that the data follow a normal distribution in both, regions with increased and reduced IC values for schizophrenic patients as compared to controls. This finding was also reported in part in previous studies. Therefore, it is unlikely that our results are biased by the filter size we used. Lastly, a DTI study investigating water diffusion changes in Wallerian degeneration showed that secondary white matter degeneration was accompanied by a large reduction in diffusion anisotropy only in regions where fibers are arranged in isolated bundles of parallel fibers. In regions where the degenerated pathway crosses other tracts paradoxically, there was almost no change in diffusion anisotropy but a significant change in the measured orientation of fibers (Pierpaoli et al., 2001). Accordingly, our results could be attributed to fiber bundle that crosses the measured area. However, in our study, the voxel dimension we measured was 3.75 mm 3.75 mm 5 mm, a dimension far too large to account for crossing or branching of fibers within a voxel. In contrast to most previous studies, we found not just regions of the brain with reduced anisotropy but also specific regions with higher anisotropy in patients with schizophrenia, as compared with the control group. Furthermore, we found a right – left asymmetry. Finally, aside from the fact that in the present study, the sample size was small, which could also introduce false positive results, our preliminary findings provide strong evidence for compromised white matter connectivity in several brain regions early in the schizophrenic disease process, which probably explains the heterogeneous symptoms of this enigmatic disease.
Acknowledgments We gratefully acknowledge the Swiss National Science Foundation for funding support (3200-059077.99 to Dr. Dierks). Further thanks are due to Regula Schweizer for performing the magnetic resonance imaging measurements and Mrs. Baechler for proofreading the manuscript. References Agartz, I., Andersson, J.L., Skare, S., 2001. Abnormal brain white matter in schizophrenia: a diffusion tensor imaging study. NeuroReport 12, 2251 – 2254. Andreasen, N.C., Paradiso, S., O’Leary, D.S., 1998. ‘‘Cognitive dysmetria’’ as an integrative theory of schizophrenia: a dysfunction in cortical – subcortical – cerebellar circuitry? Schizophr. Bull. 24, 203 – 218. Ardekani, B.A., Nierenberg, J., Hoptman, M.J., Javitt, D.C., Lim, K.O., 2003. MRI study of white matter diffusion anisotropy in schizophrenia. NeuroReport 14, 2025 – 2029.
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