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Fiber tracking of white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex in schizophrenia: A diffusion tensor imaging study
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www.sciencedirect.com European Psychiatry 24 (2009) 269e274
Original article
Fiber tracking of white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex in schizophrenia: A diffusion tensor imaging study Shinsuke Kito a,*, Jiuk Jung b, Tetsuo Kobayashi b, Yoshihiko Koga a a
Department of Neuropsychiatry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan b Department of Electrical Engineering, Graduate School of Engineering, Kyoto University, Kyoto, Japan Received 20 July 2008; received in revised form 27 November 2008; accepted 15 December 2008 Available online 4 February 2009
Abstract The goal of this study was to detect abnormalities in white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex using fiber-tracking technique. Diffusion tensor imaging was acquired in 20 patients with schizophrenia and 20 normal comparison subjects. Fiber tracking was performed on the anterior thalamic peduncle, and the tractography was used to determine the crosssectional area, mean fractional anisotropy, and standard deviation of fractional anisotropy for every step separately in the right and left hemispheres. Compared with normal subjects, patients showed a significant reduction in the cross-sectional area of the left anterior thalamic peduncle. There were no significant differences for the mean fractional anisotropy bilaterally between the two groups, but significant differences for the standard deviation of fractional anisotropy in both hemispheres. Reduction in the cross-sectional area of the left anterior thalamic peduncle suggests the presence of the failure of left-hemisphere lateralization. In schizophrenic patients a significant increase of the standard deviation of fractional anisotropy raise the possibility that the inhomogeneity of white matter integrity, which is densely or sparsely distributed by site. These findings might provide further evidence for disruption of white matter integrity between the thalamus and the prefrontal cortex in schizophrenia. Ó 2009 Elsevier Masson SAS. All rights reserved. Keywords: Diffusion tensor imaging; Tractography; Fiber tracking; Schizophrenia; Fractional anisotropy; MRI
1. Introduction Diffusion tensor imaging is a non-invasive method of measuring the diffusion phenomenon of water molecules in vivo. In the cerebral white matter, diffusion in the same direction as nerve fibers is unrestricted, whereas diffusion perpendicular to nerves fiber is restricted. By qualifying and quantifying the magnitude and direction of water diffusion in the white matter, it is possible to detect structural abnormalities in the nerve fibers [17,30]. Research on the cerebral white matter of schizophrenia patients using diffusion tensor imaging was first reported in 1998 by Buchsbaum et al. [5]. These researchers used * Corresponding author. Tel.: þ81 422 47 5511x2885; fax: þ81 422 45 4697. E-mail address: [email protected] (S. Kito). 0924-9338/$ - see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2008.12.012
magnetic resonance imaging and positron emission tomography to describe abnormalities of the white matter region in the frontal lobe and the anterior limb of the internal capsule [5]. It also became clear that, as a result of comparing a schizophrenic patient group with a healthy subject group, the former did not show a decrease in the volume of the cerebral white matter [20], but showed a decline in diffusion anisotropy that indicated structural abnormalities of the white matter integrity over a broad region [1,6,20,21]. Reduced diffusion anisotropy in the white matter region such as this is an indication of structural abnormalities in the integrity of the white matter, which is responsible for neural connectivity among the different brain regions. It supports findings obtained in research that have adopted a molecular biological approach targeting myelin and oligodendrocyte, using postmortem brains [12,13,31]. Regarding a decline in diffusion anisotropy
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in specific neuronal tract, abnormalities at the following sites have been reported: in the corpus callosum that connects the right and left hemispheres [1,6]; the uncinate fasciculus that connects the frontal lobe and the temporal lobe within the ipsilateral hemisphere [8,18,24]; the arcuate fasciculus that connects the frontal lobe and the parietal lobe [8]; the superior longitudinal fasciculus [6]; the cingulate fasciculus [19]; and the middle cerebellar peduncles [23]. It is also reported that fractional anisotropy in the left frontal white matter and middle cerebellar peduncles of schizophrenic patients are correlated with the dosages of antipsychotics [21,23]. These findings were obtained by analytical methods such as the region-of-interest technique (ROI), and voxel-based morphometry (VBM), and chiefly report on abnormalities of the neuronal tract that are primarily responsible for corticocortical connections. Recently diffusion tensor imaging studies using tractography revealed structural abnormalities of white matter integrity in the corpus callosum [26], the left uncinate fasciculus [27], and the left inferior longitudinal fasciculus [2]. Jones et al. [14,15] reported that reduction of fractional anisotropy was seen in the uncinate, superior longitudinal, and inferior fronto-occipital fasciculi, and the cingulum as compared with age-matched comparison subjects using tractography, but the difference was observed in very young schizophrenic patients, and it diminished with increasing age. On the other hand, postmortem and magnetic resonance imaging studies have revealed structural abnormalities and volume reductions in the thalamus and prefrontal cortex in schizophrenia [9,10,16,28,31]. Interestingly, several diffusion tensor imaging studies have shown abnormalities in the anterior limb of the internal capsule, suggesting disruption of white matter integrity between the thalamus and the prefrontal cortex involved in the pathophysiology of schizophrenia [5,6,7,29]. Therefore, we sought to investigate structural abnormalities in white matter integrity of the anterior thalamic peduncle connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex. The goal of this study was to detect structural abnormalities in white matter integrity of the anterior thalamic peduncle using fiber-tracking technique and the tractography (tractography-based ROI). 2. Materials and methods A total of 20 patients (11 males and 9 females) who met the DSM-IV-TR criteria of schizophrenia and 20 normal comparison subjects (11 males and 9 females) participated in this study. All subjects gave written informed consent for study participation after a full explanation of procedures. Exclusion criteria for all subjects included a history of convulsive disease, head injury, and a history of alcohol and substance dependence. In addition, the following were excluded as study subjects: those with diabetes and hypertension; those who had undergone electroconvulsive therapy; and those whose brain magnetic resonance imaging scans already showed clear abnormalities. All subjects included in this study were right-handed, and no significant differences in
age or sex were seen between the schizophrenic patients and comparison subjects. Demographic characteristics of schizophrenic patients and normal comparison subjects who participated in the present study are shown in Table 1. The mean duration of illness in the patients was 7.1 6.4 years, and the mean dosage of antipsychotics was 270 232 mg/day (chlorpromazine equivalents) [32]. Prior to implementing this study, we obtained the approval of Kyorin University School of Medicine’s Ethics Committee. Diffusion tensor imaging was conducted on a 1.5-T Intera Achieva Nova Dual (Philips Electronics). The image-taking conditions were set as follows: TR 2900 ms, TE 60 ms, NEX (the number of excitations) 6, FOV (field of view) 240 mm, voxel size 1.88 1.88 5.0 mm3, image matrix 128 128, slice thickness 5 mm, 25 slices, MPG 6 directions ([0.3333, 0.6666, 0.6666], [0.6666, 0.3333, 0.6666], [0.6666, 0.6666, 0.3333], [0.7071, 0.7071, 0], [0, 0.7071, 0.7071], [0.7071, 0, 0.7071]), b value 1000 s/mm2. Fractional anisotropy measures were calculated as described by Basser et al. [3]. The present study targeted the anterior thalamic peduncle, which is a neuronal tract that runs from the mediodorsal of the thalamus towards the prefrontal cortex (mainly the dorsolateral prefrontal cortex) by way of the anterior limb of the internal capsule. As for setting the region of interest in the target nervous bundle, we first established the cross-section of the internal capsule in the coronal section that includes the anterior commissure as the starting region for fiber tracking, and established the coronal section that includes the anterior genu of the corpus callosum as the ending region for fiber tracking. Each of these starting regions and ending regions in the right and left hemispheres were adjusted separately back and forth within a range of 8 mm, after which fiber tracking was performed. The sites where the largest number of streamlines could be tracked were finally selected as the starting and ending regions for the fiber tracking, and, based on these, tractography was applied (Fig. 1). In identifying the fiber bundles in the regions of interest, we dispersed the Table 1 Demographic characteristics of schizophrenia patients and normal comparison subjects. Characteristics
Age (years) Sex Male Female Antipsychotics Risperidone Olanzapine Aripiprazole Quetiapine Others None
Comparison subjects
Schizophrenia patients
Statistical analysis
Mean
SD
Mean
SD
t
df
p
32.5 N
7.4
32.9 N
8.6
0.14 c
38 df
0.891 p
0.00
1
1.000
11 9
11 9 7 4 3 1 3 3
Others include perphenazine, haloperidol, and chlorpromazine. One out of 20 schizophrenia patients was receiving two antipsychotics.
S. Kito et al. / European Psychiatry 24 (2009) 269e274
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hemisphere as the within-subjects factor were performed for the cross-sectional areas, mean fractional anisotropy, and standard deviation of fractional anisotropy in the anterior thalamic peduncle. In the case of significant between-group effects for patients and comparisons, within-subjects effects for hemispheres, or group-by-hemisphere interactions, t-tests were used to individually compare group and hemisphere asymmetry differences. Statistical analysis was conducted using SPSS for Windows 14.0 (SPSS Inc., Chicago, Illinois), with the level of statistical significance set at p < 0.05. 3. Results
Fig. 1. The cross-section of the internal capsule in the coronal section, which includes the anterior commissure, was established as the starting region for fiber tracking (A). The coronal section that includes the anterior genu of the corpus callosum was established as the ending region for fiber tracking (B). The starting and ending regions were adjusted back and forth, each within the range of 8 mm (shown as boxes), and the sites where the largest number of streamlines could be tracked were finally made the starting and ending regions for fiber tracking.
tracking starting points evenly on the plane of the starting region at a rate of 4 points/mm2. For fiber tracking, the Streamlines Tracking Technique [4,11,22] and the Rungee Kutta of the fourth order [25] were used, while the step width was set at 0.5 mm. Fiber trajectories were terminated at voxel with fractional anisotropy less than 0.25, or when the turning angle between adjacent steps was greater than 45 . To identify and erase erroneously tracked streamlines, we selected, separately for the right and left hemispheres, out of the extracted streamline groups, those whose streamline length was the shortest, and used that length as the baseline streamline length. Of those including streamline groups of the right and left hemispheres, any streamline measurement whose length exceeded 105% of the baseline streamline length were judged to show erroneous tracking results and were thus eliminated from the streamline group. Next, from the tractographs that had been created, the cross-sectional area of the neuronal tract in the starting region, and the mean fractional anisotropy of the neuronal tract were calculated separately for the right and left hemispheres. Moreover, we calculated the standard deviations of fractional anisotropy for each step during the streamline’s process flow, from the starting region to the ending region of fiber tracking, separately for the right and left hemispheres in the schizophrenic subject group and the comparison subject group. Creation of tractographs, and quantification of the cross-sectional area, mean fractional anisotropy and standard deviation of fractional anisotropy such as these were done using the Matlab 7.1 program created by authors Jung and Kobayashi. Two-way repeated-measures analyses of variance (ANOVAs) with group as the between-group factor and
Table 2 shows the cross-sectional areas of the anterior thalamic peduncle’s starting regions, mean fractional anisotropy and standard deviation of fractional anisotropy of the schizophrenic patient group (N ¼ 20) and the comparison subject group (N ¼ 20). The results analyzed using two-way repeated-measures ANOVAs with group as the between-group factor and hemisphere as the within-subjects factor are shown in Table 2. For the cross-sectional areas, ANOVAs showed significant between-group effects and group-by-hemisphere interactions, but no significant within-subjects effects. ANOVAs for the mean fractional anisotropy showed significant within-subjects effects, but no significant between-group effects and no groupby-hemisphere interactions. ANOVAs for the standard deviation of fractional anisotropy showed significant between-group effects and within-subjects effects, but no significant groupby-hemisphere interactions. Since significant group effects and group-by-hemisphere interactions in the cross-sectional area of the anterior thalamic Table 2 Cross-sectional area, fractional anisotropy, and standard deviation of fractional anisotropy in the anterior thalamic peduncle of schizophrenia patients and normal comparison subjects. Comparison subjects (N ¼ 20)
Schizophrenia patients (N ¼ 20)
Mean
Mean
SD
15.75 18.74
10.96 13.63
SD 2
Cross-sectional area (mm ) Left 33.98 20.24 Right 22.59 12.76 Fractional anisotropy Left 0.447 0.036 Right 0.431 0.028 Standard deviation of fractional anisotropy Left 0.089 0.040 Right 0.075 0.032
0.443 0.432
0.054 0.036
0.119 0.099
0.040 0.034
ANOVA Group effect F (df ¼ 1, 38)
p
Hemisphere effect
Interaction
F (df ¼ 1, 38)
p
F (df ¼ 1, 38)
p
0.135
6.81
0.013
0.042
0.18
0.675
0.041
0.15
0.700
2
Cross-sectional area (mm ) 8.47 0.006 2.33 Fractional anisotropy 0.025 0.876 4.44 Standard deviation of fractional anisotropy 10.99 0.002 4.48
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peduncle were seen, these data were analyzed separately for the right and left hemispheres using independent t-tests. Compared with the comparison subject group, the schizophrenic patient group had significantly smaller cross-sectional area of the anterior thalamic peduncle of the left hemisphere (t ¼ 3.54, df ¼ 38, p ¼ 0.001), but showed no significant difference in the right hemisphere (t ¼ 0.92, df ¼ 38, p ¼ 0.362). For the mean fractional anisotropy significant hemisphere effects were found, and further these hemisphere asymmetries were analyzed using paired t-tests individually in the two groups. However, there were no significant differences for hemisphere asymmetries in both groups (comparisons: t ¼ 2.07, df ¼ 19, p ¼ 0.052; patients: t ¼ 1.06, df ¼ 19, p ¼ 0.301). Because of significant group effects and hemisphere effects in the standard deviation of fractional anisotropy with ANOVAs, the two groups were compared using independent t-tests separately for the right and left hemispheres, and showed significant differences in both the right and left hemispheres (right: t ¼ 2.32, df ¼ 38, p ¼ 0.026; left: t ¼ 2.40, df ¼ 38, p ¼ 0.021). However, there were no significant differences between the right and left hemispheres in both groups, using paired t-tests for hemisphere symmetries (comparisons: t ¼ 1.29, df ¼ 19, p ¼ 0.213; patients: t ¼ 1.69, df ¼ 19, p ¼ 0.107). To evaluate the relationships between the dosages of antipsychotics and the mean fractional anisotropy, we analyzed these data in the schizophrenic patients using Pearson’s product-moment correlation coefficient. However, there were no correlations between the dosages of antipsychotics and the fractional anisotropy (right: r ¼ 0.21, p ¼ 0.38; left: r ¼ 0.33, p ¼ 0.15). 4. Discussion In the present study, we created tractographs of the anterior thalamic peduncle, which is a neuronal tract that runs from the mediodorsal nucleus of the thalamus towards the prefrontal cortex by way of the anterior limb of the internal capsule, and determined the quantity of the anterior thalamic peduncle’s cross-sectional area, mean fractional anisotropy, and standard deviation of fractional anisotropy. Compared with the comparison subject group, the schizophrenic patient group had a smaller cross-sectional area of the anterior thalamic peduncle in both hemispheres, with a significant difference also seen in the left hemisphere. In addition, the schizophrenic patient group showed a smaller cross-sectional area of the anterior thalamic peduncle in the left hemisphere than in the right hemisphere, although the comparison subject group tended to show a larger area in the left hemisphere. On the other hand, the mean fractional anisotropy of the anterior thalamic peduncle revealed no significant differences between the two groups for both hemispheres. No significant differences were seen in the comparison of the two hemispheres using paired t-tests. Park et al. [24] used the VBM technique to determine the quantity of fractional anisotropy in the schizophrenic patient group and the comparison subject group, and reported that the
asymmetry in the right and left hemispheres seen in the white matter region and the neuronal tract, which should inherently be noted in the comparison subject group, was not seen in the schizophrenic patient group in the anterior limb of the internal capsule, the uncinate fasciculus, and the superior cerebellar peduncle. The authors also reported that asymmetry had been decreased in other white matter regions and neuronal tract [24]. There are also other reports that describe the reduction of fractional anisotropy in the left hemisphere’s uncinate fasciculus and arcuate fasciculus among a schizophrenic patient group as compared with a comparison subject group, raising the possibility of fronto-temporal and fronto-parietal neural disconnectivity [8]. As an example of a study that used the VBM technique to compare first-episode schizophrenic patients and healthy individuals, there is a report by Szeszko et al. [29] who described the reduction of fractional anisotropy among the schizophrenic patient group in the left internal capsule and left-hemisphere white matter of the middle frontal gyrus and posterior superior temporal gyrus [29]. These findings based on diffusion tensor imaging studies suggest that the neural disconnectivity among the different brain regions as well as the neuro-developmental abnormalities of left-hemisphere lateralization are involved in the pathophysiology of schizophrenia. The results of this study have revealed that the cross-sectional area of the neuronal tract that connects the mediodorsal nucleus of the thalamus and the prefrontal cortex is smaller in the schizophrenic patient group than in the comparison subject group, and that this tendency is more pronounced in the left hemisphere significantly. These findings support the involvement of the failure of the left-hemisphere lateralization causing a reduction in white matter integrity, particularly in the left hemisphere, in the neuronal tract that connects the thalamic mediodorsal nucleus and the prefrontal cortex. Quantification of the length of the anterior thalamic peduncle was not carried out in this study. However, Buchsbaum et al. [7] traced neuronal tract that runs from the anterior limb of the internal capsule to the frontal lobe, and reported that, compared with the comparison subject group, the schizophrenic patient group had significantly shorter neuronal tract, and remarked on the disruption of the frontalestriatalethalamic pathway. As mentioned above in the introduction, postmortem and magnetic resonance imaging studies showed abnormalities and volume reductions in the prefrontal cortex [28,31] and the thalamus, especially the mediodorsal nucleus [9,10,16]. Lower fractional anisotropy of the anterior thalamic peduncle suggests disruption of the fronto-thalamic and thalamo-frontal pathways involved in the pathophysiology of schizophrenia [5e7,29]. Fractional anisotropy in the present study was not correlated with the dosages of antipsychotics, and there was no significant difference for the fractional anisotropy between the schizophrenic patient group and comparison subject group. A significant difference in standard deviation of fractional anisotropy was seen between the schizophrenic patient group and the comparison subject group in both hemispheres. The meaning of standard deviation of fractional anisotropy in this study is that, because the standard deviation of fractional
S. Kito et al. / European Psychiatry 24 (2009) 269e274
anisotropy in conducting the anterior thalamic peduncle’s fiber tracking is for every 0.5 mm of the step width, a large standard deviation indicates a large difference in the value of fractional anisotropy for every 0.5 mm during the course of the anterior thalamic peduncle’s process from the starting region to the ending region. Conversely, a small standard deviation suggests a small difference in the fractional anisotropy value for every 0.5 mm during the fiber’s course, raising the possibility that white matter integrity is even more homogenous. The anterior thalamic peduncle of schizophrenic patients participated in this study showed significant differences in standard deviation of fractional anisotropy for both hemispheres as compared with the comparison subject group, but no significant difference in mean fractional anisotropy. These findings suggest that the value of fractional anisotropy is large or small, depending on the site of the white matter integrity of the anterior thalamic peduncle from the starting region to the ending region, raising the possibility of structural inhomogeneity of the white matter integrity, which is densely or sparsely distributed by site. There are some possible limitations in the present study. Since diffusion tensor imaging was acquired with six directions, 5 mm thick slices, and a highly anisotropic voxel, there is a possibility that the image resolution might be insufficient to reconstruct tractography, limiting to some degree partial volume effects. When diffusion tensor imaging in schizophrenic patients who enrolled in this study was acquired, some patients were receiving antipsychotic therapy. There is a possibility that the results have been influenced by the actions of the antipsychotic drugs. Regarding this, this study showed a significant decrease in the cross-sectional area of the anterior thalamic peduncle in the left hemisphere, and it is unlikely that exposure to antipsychotic drugs would induce a reduction in the white matter integrity focusing on a particular hemisphere. Moreover, the mean fractional anisotropy was approximately equivalent between the schizophrenic patient group and the comparison subject group in both hemispheres, with no significant differences. Therefore, it is considered that the influence of the fractional anisotropy values attributable to antipsychotic drugs was not reflected in the results obtained in this study. Additionally, several earlier studies showed a reduction in fractional anisotropy in the anterior limb of the internal capsule in schizophrenic patients [5,6,29], but we could not confirm a significant reduction in mean fractional anisotropy in the anterior thalamic peduncle for both hemispheres as compared with comparison subjects. The reason for discrepancy in the present study might be accounted for by calculating mean fractional anisotropy of the entire anterior thalamic peduncle from the starting region to the ending region, and technical parameters of fiber tracking performed on this study. To determine whether the findings of this study are the specificity in the anterior thalamic peduncle, further studies are necessary for a comparison with other white matter tracts. To our knowledge, this is the first study to perform fiber tracking of the anterior thalamic peduncle that connects the mediodorsal nucleus of the thalamus and the prefrontal cortex.
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The results of this study have revealed a reduction in the crosssectional area of the anterior thalamic peduncle in the left hemisphere of schizophrenia patients, suggesting the presence of the failure of left-hemisphere lateralization, and raise the possibility that the inhomogeneity of white matter integrity, which is densely or sparsely distributed by site, in the bilateral anterior thalamic peduncles. These findings might provide further evidence for disruption of white matter integrity between the thalamus and the prefrontal cortex in schizophrenia.
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Original article
Fiber tracking of white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex in schizophrenia: A diffusion tensor imaging study Shinsuke Kito a,*, Jiuk Jung b, Tetsuo Kobayashi b, Yoshihiko Koga a a
Department of Neuropsychiatry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan b Department of Electrical Engineering, Graduate School of Engineering, Kyoto University, Kyoto, Japan Received 20 July 2008; received in revised form 27 November 2008; accepted 15 December 2008 Available online 4 February 2009
Abstract The goal of this study was to detect abnormalities in white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex using fiber-tracking technique. Diffusion tensor imaging was acquired in 20 patients with schizophrenia and 20 normal comparison subjects. Fiber tracking was performed on the anterior thalamic peduncle, and the tractography was used to determine the crosssectional area, mean fractional anisotropy, and standard deviation of fractional anisotropy for every step separately in the right and left hemispheres. Compared with normal subjects, patients showed a significant reduction in the cross-sectional area of the left anterior thalamic peduncle. There were no significant differences for the mean fractional anisotropy bilaterally between the two groups, but significant differences for the standard deviation of fractional anisotropy in both hemispheres. Reduction in the cross-sectional area of the left anterior thalamic peduncle suggests the presence of the failure of left-hemisphere lateralization. In schizophrenic patients a significant increase of the standard deviation of fractional anisotropy raise the possibility that the inhomogeneity of white matter integrity, which is densely or sparsely distributed by site. These findings might provide further evidence for disruption of white matter integrity between the thalamus and the prefrontal cortex in schizophrenia. Ó 2009 Elsevier Masson SAS. All rights reserved. Keywords: Diffusion tensor imaging; Tractography; Fiber tracking; Schizophrenia; Fractional anisotropy; MRI
1. Introduction Diffusion tensor imaging is a non-invasive method of measuring the diffusion phenomenon of water molecules in vivo. In the cerebral white matter, diffusion in the same direction as nerve fibers is unrestricted, whereas diffusion perpendicular to nerves fiber is restricted. By qualifying and quantifying the magnitude and direction of water diffusion in the white matter, it is possible to detect structural abnormalities in the nerve fibers [17,30]. Research on the cerebral white matter of schizophrenia patients using diffusion tensor imaging was first reported in 1998 by Buchsbaum et al. [5]. These researchers used * Corresponding author. Tel.: þ81 422 47 5511x2885; fax: þ81 422 45 4697. E-mail address: [email protected] (S. Kito). 0924-9338/$ - see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2008.12.012
magnetic resonance imaging and positron emission tomography to describe abnormalities of the white matter region in the frontal lobe and the anterior limb of the internal capsule [5]. It also became clear that, as a result of comparing a schizophrenic patient group with a healthy subject group, the former did not show a decrease in the volume of the cerebral white matter [20], but showed a decline in diffusion anisotropy that indicated structural abnormalities of the white matter integrity over a broad region [1,6,20,21]. Reduced diffusion anisotropy in the white matter region such as this is an indication of structural abnormalities in the integrity of the white matter, which is responsible for neural connectivity among the different brain regions. It supports findings obtained in research that have adopted a molecular biological approach targeting myelin and oligodendrocyte, using postmortem brains [12,13,31]. Regarding a decline in diffusion anisotropy
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in specific neuronal tract, abnormalities at the following sites have been reported: in the corpus callosum that connects the right and left hemispheres [1,6]; the uncinate fasciculus that connects the frontal lobe and the temporal lobe within the ipsilateral hemisphere [8,18,24]; the arcuate fasciculus that connects the frontal lobe and the parietal lobe [8]; the superior longitudinal fasciculus [6]; the cingulate fasciculus [19]; and the middle cerebellar peduncles [23]. It is also reported that fractional anisotropy in the left frontal white matter and middle cerebellar peduncles of schizophrenic patients are correlated with the dosages of antipsychotics [21,23]. These findings were obtained by analytical methods such as the region-of-interest technique (ROI), and voxel-based morphometry (VBM), and chiefly report on abnormalities of the neuronal tract that are primarily responsible for corticocortical connections. Recently diffusion tensor imaging studies using tractography revealed structural abnormalities of white matter integrity in the corpus callosum [26], the left uncinate fasciculus [27], and the left inferior longitudinal fasciculus [2]. Jones et al. [14,15] reported that reduction of fractional anisotropy was seen in the uncinate, superior longitudinal, and inferior fronto-occipital fasciculi, and the cingulum as compared with age-matched comparison subjects using tractography, but the difference was observed in very young schizophrenic patients, and it diminished with increasing age. On the other hand, postmortem and magnetic resonance imaging studies have revealed structural abnormalities and volume reductions in the thalamus and prefrontal cortex in schizophrenia [9,10,16,28,31]. Interestingly, several diffusion tensor imaging studies have shown abnormalities in the anterior limb of the internal capsule, suggesting disruption of white matter integrity between the thalamus and the prefrontal cortex involved in the pathophysiology of schizophrenia [5,6,7,29]. Therefore, we sought to investigate structural abnormalities in white matter integrity of the anterior thalamic peduncle connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex. The goal of this study was to detect structural abnormalities in white matter integrity of the anterior thalamic peduncle using fiber-tracking technique and the tractography (tractography-based ROI). 2. Materials and methods A total of 20 patients (11 males and 9 females) who met the DSM-IV-TR criteria of schizophrenia and 20 normal comparison subjects (11 males and 9 females) participated in this study. All subjects gave written informed consent for study participation after a full explanation of procedures. Exclusion criteria for all subjects included a history of convulsive disease, head injury, and a history of alcohol and substance dependence. In addition, the following were excluded as study subjects: those with diabetes and hypertension; those who had undergone electroconvulsive therapy; and those whose brain magnetic resonance imaging scans already showed clear abnormalities. All subjects included in this study were right-handed, and no significant differences in
age or sex were seen between the schizophrenic patients and comparison subjects. Demographic characteristics of schizophrenic patients and normal comparison subjects who participated in the present study are shown in Table 1. The mean duration of illness in the patients was 7.1 6.4 years, and the mean dosage of antipsychotics was 270 232 mg/day (chlorpromazine equivalents) [32]. Prior to implementing this study, we obtained the approval of Kyorin University School of Medicine’s Ethics Committee. Diffusion tensor imaging was conducted on a 1.5-T Intera Achieva Nova Dual (Philips Electronics). The image-taking conditions were set as follows: TR 2900 ms, TE 60 ms, NEX (the number of excitations) 6, FOV (field of view) 240 mm, voxel size 1.88 1.88 5.0 mm3, image matrix 128 128, slice thickness 5 mm, 25 slices, MPG 6 directions ([0.3333, 0.6666, 0.6666], [0.6666, 0.3333, 0.6666], [0.6666, 0.6666, 0.3333], [0.7071, 0.7071, 0], [0, 0.7071, 0.7071], [0.7071, 0, 0.7071]), b value 1000 s/mm2. Fractional anisotropy measures were calculated as described by Basser et al. [3]. The present study targeted the anterior thalamic peduncle, which is a neuronal tract that runs from the mediodorsal of the thalamus towards the prefrontal cortex (mainly the dorsolateral prefrontal cortex) by way of the anterior limb of the internal capsule. As for setting the region of interest in the target nervous bundle, we first established the cross-section of the internal capsule in the coronal section that includes the anterior commissure as the starting region for fiber tracking, and established the coronal section that includes the anterior genu of the corpus callosum as the ending region for fiber tracking. Each of these starting regions and ending regions in the right and left hemispheres were adjusted separately back and forth within a range of 8 mm, after which fiber tracking was performed. The sites where the largest number of streamlines could be tracked were finally selected as the starting and ending regions for the fiber tracking, and, based on these, tractography was applied (Fig. 1). In identifying the fiber bundles in the regions of interest, we dispersed the Table 1 Demographic characteristics of schizophrenia patients and normal comparison subjects. Characteristics
Age (years) Sex Male Female Antipsychotics Risperidone Olanzapine Aripiprazole Quetiapine Others None
Comparison subjects
Schizophrenia patients
Statistical analysis
Mean
SD
Mean
SD
t
df
p
32.5 N
7.4
32.9 N
8.6
0.14 c
38 df
0.891 p
0.00
1
1.000
11 9
11 9 7 4 3 1 3 3
Others include perphenazine, haloperidol, and chlorpromazine. One out of 20 schizophrenia patients was receiving two antipsychotics.
S. Kito et al. / European Psychiatry 24 (2009) 269e274
271
hemisphere as the within-subjects factor were performed for the cross-sectional areas, mean fractional anisotropy, and standard deviation of fractional anisotropy in the anterior thalamic peduncle. In the case of significant between-group effects for patients and comparisons, within-subjects effects for hemispheres, or group-by-hemisphere interactions, t-tests were used to individually compare group and hemisphere asymmetry differences. Statistical analysis was conducted using SPSS for Windows 14.0 (SPSS Inc., Chicago, Illinois), with the level of statistical significance set at p < 0.05. 3. Results
Fig. 1. The cross-section of the internal capsule in the coronal section, which includes the anterior commissure, was established as the starting region for fiber tracking (A). The coronal section that includes the anterior genu of the corpus callosum was established as the ending region for fiber tracking (B). The starting and ending regions were adjusted back and forth, each within the range of 8 mm (shown as boxes), and the sites where the largest number of streamlines could be tracked were finally made the starting and ending regions for fiber tracking.
tracking starting points evenly on the plane of the starting region at a rate of 4 points/mm2. For fiber tracking, the Streamlines Tracking Technique [4,11,22] and the Rungee Kutta of the fourth order [25] were used, while the step width was set at 0.5 mm. Fiber trajectories were terminated at voxel with fractional anisotropy less than 0.25, or when the turning angle between adjacent steps was greater than 45 . To identify and erase erroneously tracked streamlines, we selected, separately for the right and left hemispheres, out of the extracted streamline groups, those whose streamline length was the shortest, and used that length as the baseline streamline length. Of those including streamline groups of the right and left hemispheres, any streamline measurement whose length exceeded 105% of the baseline streamline length were judged to show erroneous tracking results and were thus eliminated from the streamline group. Next, from the tractographs that had been created, the cross-sectional area of the neuronal tract in the starting region, and the mean fractional anisotropy of the neuronal tract were calculated separately for the right and left hemispheres. Moreover, we calculated the standard deviations of fractional anisotropy for each step during the streamline’s process flow, from the starting region to the ending region of fiber tracking, separately for the right and left hemispheres in the schizophrenic subject group and the comparison subject group. Creation of tractographs, and quantification of the cross-sectional area, mean fractional anisotropy and standard deviation of fractional anisotropy such as these were done using the Matlab 7.1 program created by authors Jung and Kobayashi. Two-way repeated-measures analyses of variance (ANOVAs) with group as the between-group factor and
Table 2 shows the cross-sectional areas of the anterior thalamic peduncle’s starting regions, mean fractional anisotropy and standard deviation of fractional anisotropy of the schizophrenic patient group (N ¼ 20) and the comparison subject group (N ¼ 20). The results analyzed using two-way repeated-measures ANOVAs with group as the between-group factor and hemisphere as the within-subjects factor are shown in Table 2. For the cross-sectional areas, ANOVAs showed significant between-group effects and group-by-hemisphere interactions, but no significant within-subjects effects. ANOVAs for the mean fractional anisotropy showed significant within-subjects effects, but no significant between-group effects and no groupby-hemisphere interactions. ANOVAs for the standard deviation of fractional anisotropy showed significant between-group effects and within-subjects effects, but no significant groupby-hemisphere interactions. Since significant group effects and group-by-hemisphere interactions in the cross-sectional area of the anterior thalamic Table 2 Cross-sectional area, fractional anisotropy, and standard deviation of fractional anisotropy in the anterior thalamic peduncle of schizophrenia patients and normal comparison subjects. Comparison subjects (N ¼ 20)
Schizophrenia patients (N ¼ 20)
Mean
Mean
SD
15.75 18.74
10.96 13.63
SD 2
Cross-sectional area (mm ) Left 33.98 20.24 Right 22.59 12.76 Fractional anisotropy Left 0.447 0.036 Right 0.431 0.028 Standard deviation of fractional anisotropy Left 0.089 0.040 Right 0.075 0.032
0.443 0.432
0.054 0.036
0.119 0.099
0.040 0.034
ANOVA Group effect F (df ¼ 1, 38)
p
Hemisphere effect
Interaction
F (df ¼ 1, 38)
p
F (df ¼ 1, 38)
p
0.135
6.81
0.013
0.042
0.18
0.675
0.041
0.15
0.700
2
Cross-sectional area (mm ) 8.47 0.006 2.33 Fractional anisotropy 0.025 0.876 4.44 Standard deviation of fractional anisotropy 10.99 0.002 4.48
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peduncle were seen, these data were analyzed separately for the right and left hemispheres using independent t-tests. Compared with the comparison subject group, the schizophrenic patient group had significantly smaller cross-sectional area of the anterior thalamic peduncle of the left hemisphere (t ¼ 3.54, df ¼ 38, p ¼ 0.001), but showed no significant difference in the right hemisphere (t ¼ 0.92, df ¼ 38, p ¼ 0.362). For the mean fractional anisotropy significant hemisphere effects were found, and further these hemisphere asymmetries were analyzed using paired t-tests individually in the two groups. However, there were no significant differences for hemisphere asymmetries in both groups (comparisons: t ¼ 2.07, df ¼ 19, p ¼ 0.052; patients: t ¼ 1.06, df ¼ 19, p ¼ 0.301). Because of significant group effects and hemisphere effects in the standard deviation of fractional anisotropy with ANOVAs, the two groups were compared using independent t-tests separately for the right and left hemispheres, and showed significant differences in both the right and left hemispheres (right: t ¼ 2.32, df ¼ 38, p ¼ 0.026; left: t ¼ 2.40, df ¼ 38, p ¼ 0.021). However, there were no significant differences between the right and left hemispheres in both groups, using paired t-tests for hemisphere symmetries (comparisons: t ¼ 1.29, df ¼ 19, p ¼ 0.213; patients: t ¼ 1.69, df ¼ 19, p ¼ 0.107). To evaluate the relationships between the dosages of antipsychotics and the mean fractional anisotropy, we analyzed these data in the schizophrenic patients using Pearson’s product-moment correlation coefficient. However, there were no correlations between the dosages of antipsychotics and the fractional anisotropy (right: r ¼ 0.21, p ¼ 0.38; left: r ¼ 0.33, p ¼ 0.15). 4. Discussion In the present study, we created tractographs of the anterior thalamic peduncle, which is a neuronal tract that runs from the mediodorsal nucleus of the thalamus towards the prefrontal cortex by way of the anterior limb of the internal capsule, and determined the quantity of the anterior thalamic peduncle’s cross-sectional area, mean fractional anisotropy, and standard deviation of fractional anisotropy. Compared with the comparison subject group, the schizophrenic patient group had a smaller cross-sectional area of the anterior thalamic peduncle in both hemispheres, with a significant difference also seen in the left hemisphere. In addition, the schizophrenic patient group showed a smaller cross-sectional area of the anterior thalamic peduncle in the left hemisphere than in the right hemisphere, although the comparison subject group tended to show a larger area in the left hemisphere. On the other hand, the mean fractional anisotropy of the anterior thalamic peduncle revealed no significant differences between the two groups for both hemispheres. No significant differences were seen in the comparison of the two hemispheres using paired t-tests. Park et al. [24] used the VBM technique to determine the quantity of fractional anisotropy in the schizophrenic patient group and the comparison subject group, and reported that the
asymmetry in the right and left hemispheres seen in the white matter region and the neuronal tract, which should inherently be noted in the comparison subject group, was not seen in the schizophrenic patient group in the anterior limb of the internal capsule, the uncinate fasciculus, and the superior cerebellar peduncle. The authors also reported that asymmetry had been decreased in other white matter regions and neuronal tract [24]. There are also other reports that describe the reduction of fractional anisotropy in the left hemisphere’s uncinate fasciculus and arcuate fasciculus among a schizophrenic patient group as compared with a comparison subject group, raising the possibility of fronto-temporal and fronto-parietal neural disconnectivity [8]. As an example of a study that used the VBM technique to compare first-episode schizophrenic patients and healthy individuals, there is a report by Szeszko et al. [29] who described the reduction of fractional anisotropy among the schizophrenic patient group in the left internal capsule and left-hemisphere white matter of the middle frontal gyrus and posterior superior temporal gyrus [29]. These findings based on diffusion tensor imaging studies suggest that the neural disconnectivity among the different brain regions as well as the neuro-developmental abnormalities of left-hemisphere lateralization are involved in the pathophysiology of schizophrenia. The results of this study have revealed that the cross-sectional area of the neuronal tract that connects the mediodorsal nucleus of the thalamus and the prefrontal cortex is smaller in the schizophrenic patient group than in the comparison subject group, and that this tendency is more pronounced in the left hemisphere significantly. These findings support the involvement of the failure of the left-hemisphere lateralization causing a reduction in white matter integrity, particularly in the left hemisphere, in the neuronal tract that connects the thalamic mediodorsal nucleus and the prefrontal cortex. Quantification of the length of the anterior thalamic peduncle was not carried out in this study. However, Buchsbaum et al. [7] traced neuronal tract that runs from the anterior limb of the internal capsule to the frontal lobe, and reported that, compared with the comparison subject group, the schizophrenic patient group had significantly shorter neuronal tract, and remarked on the disruption of the frontalestriatalethalamic pathway. As mentioned above in the introduction, postmortem and magnetic resonance imaging studies showed abnormalities and volume reductions in the prefrontal cortex [28,31] and the thalamus, especially the mediodorsal nucleus [9,10,16]. Lower fractional anisotropy of the anterior thalamic peduncle suggests disruption of the fronto-thalamic and thalamo-frontal pathways involved in the pathophysiology of schizophrenia [5e7,29]. Fractional anisotropy in the present study was not correlated with the dosages of antipsychotics, and there was no significant difference for the fractional anisotropy between the schizophrenic patient group and comparison subject group. A significant difference in standard deviation of fractional anisotropy was seen between the schizophrenic patient group and the comparison subject group in both hemispheres. The meaning of standard deviation of fractional anisotropy in this study is that, because the standard deviation of fractional
S. Kito et al. / European Psychiatry 24 (2009) 269e274
anisotropy in conducting the anterior thalamic peduncle’s fiber tracking is for every 0.5 mm of the step width, a large standard deviation indicates a large difference in the value of fractional anisotropy for every 0.5 mm during the course of the anterior thalamic peduncle’s process from the starting region to the ending region. Conversely, a small standard deviation suggests a small difference in the fractional anisotropy value for every 0.5 mm during the fiber’s course, raising the possibility that white matter integrity is even more homogenous. The anterior thalamic peduncle of schizophrenic patients participated in this study showed significant differences in standard deviation of fractional anisotropy for both hemispheres as compared with the comparison subject group, but no significant difference in mean fractional anisotropy. These findings suggest that the value of fractional anisotropy is large or small, depending on the site of the white matter integrity of the anterior thalamic peduncle from the starting region to the ending region, raising the possibility of structural inhomogeneity of the white matter integrity, which is densely or sparsely distributed by site. There are some possible limitations in the present study. Since diffusion tensor imaging was acquired with six directions, 5 mm thick slices, and a highly anisotropic voxel, there is a possibility that the image resolution might be insufficient to reconstruct tractography, limiting to some degree partial volume effects. When diffusion tensor imaging in schizophrenic patients who enrolled in this study was acquired, some patients were receiving antipsychotic therapy. There is a possibility that the results have been influenced by the actions of the antipsychotic drugs. Regarding this, this study showed a significant decrease in the cross-sectional area of the anterior thalamic peduncle in the left hemisphere, and it is unlikely that exposure to antipsychotic drugs would induce a reduction in the white matter integrity focusing on a particular hemisphere. Moreover, the mean fractional anisotropy was approximately equivalent between the schizophrenic patient group and the comparison subject group in both hemispheres, with no significant differences. Therefore, it is considered that the influence of the fractional anisotropy values attributable to antipsychotic drugs was not reflected in the results obtained in this study. Additionally, several earlier studies showed a reduction in fractional anisotropy in the anterior limb of the internal capsule in schizophrenic patients [5,6,29], but we could not confirm a significant reduction in mean fractional anisotropy in the anterior thalamic peduncle for both hemispheres as compared with comparison subjects. The reason for discrepancy in the present study might be accounted for by calculating mean fractional anisotropy of the entire anterior thalamic peduncle from the starting region to the ending region, and technical parameters of fiber tracking performed on this study. To determine whether the findings of this study are the specificity in the anterior thalamic peduncle, further studies are necessary for a comparison with other white matter tracts. To our knowledge, this is the first study to perform fiber tracking of the anterior thalamic peduncle that connects the mediodorsal nucleus of the thalamus and the prefrontal cortex.
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The results of this study have revealed a reduction in the crosssectional area of the anterior thalamic peduncle in the left hemisphere of schizophrenia patients, suggesting the presence of the failure of left-hemisphere lateralization, and raise the possibility that the inhomogeneity of white matter integrity, which is densely or sparsely distributed by site, in the bilateral anterior thalamic peduncles. These findings might provide further evidence for disruption of white matter integrity between the thalamus and the prefrontal cortex in schizophrenia.
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