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Shape deformation of the insula in schizophrenia
www.elsevier.com/locate/ynimg NeuroImage 32 (2006) 220 – 227
Shape deformation of the insula in schizophrenia Dong-Pyo Jang,a,e Jae-Jin Kim,b,c,d,* Tae-Sub Chung,d Suk Kyoon An,b,c Young Chul Jung,b,c Jun-Kee Lee,a Jong-Min Lee,a In-Young Kim,a and Sun I. Kim a a
Department of Biomedical Engineering, Hanyang University, Seoul, Korea Department of Psychiatry, Yonsei University College of Medicine, Seoul, Korea c Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Korea d Department of Diagnostic Radiology, Yonsei University College of Medicine, Seoul, Korea e Neuroscience Research Institute, Gachon Medical School, Seoul, Korea b
Received 29 October 2005; revised 22 December 2005; accepted 25 January 2006 Available online 26 May 2006 Schizophrenia has been conceptualized to be a neurodevelopmental disorder. Neuroimaging evidence was generally findings of volumetric reductions in various brain structures. The shape analysis of the insula can uncover unique structural deformity in the neurodevelopmental disorder, which cannot be revealed from a simple volume measurement. The objective of this study was to demonstrate a subtle change of the insula in schizophrenia using our special shape analysis technique. Subjects were 23 patients with schizophrenia and 23 normal healthy subjects. A landmark-based structural and surface shape analysis of the insula was performed using high-spatial resolution magnetic resonance imaging. A characteristic finding was that the frontotemporal sides of the right insula were deformed in the patients with schizophrenia compared with normal controls. This deformation can be associated with abnormal development of the frontal and temporal lobes in schizophrenia. D 2006 Elsevier Inc. All rights reserved. Keywords: Schizophrenia; Insula; MRI; Shape analysis
Introduction Schizophrenia is a devastating mental illness that usually produces chronic disability for affected individuals. It has been conceptualized that the pathogenesis of schizophrenia may be neurodevelopmental in nature (Bloom, 1993; Weinberger, 1995). As suggested by the term Fneurodevelopment_, the structural abnormalities of brain volume observed in schizophrenia could be influenced by intrauterine, perinatal, and extrauterine insults, as well as neurobiological maturational processes. Magnetic resonance (MR) studies have demonstrated volume reductions in
* Corresponding author. Department of Psychiatry, Yonsei University College of Medicine, Severance Mental Health Hospital, 696-6 Tanbuldong Gwangju-si, Geonggi-do 464-100, Korea. Fax: +82 31 761 7582. E-mail address: [email protected] (J.-J. Kim). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.01.032
various brain structures in schizophrenia (Shenton et al., 2001). However, simple MR volumetric reductions are not enough to be evidence of the neurodevelopmental abnormality because they are also observed in neurodegenerative cortical atrophy. More advanced morphometric tools are needed in order to elucidate structural deformities derived from the abnormal neurodevelopmental processes. A shape analysis is an example of such a study. Abnormal brain morphology in schizophrenia has been demonstrated in a subcortical structure such as the hippocampus (Shenton et al., 2002; Lee et al., 2004) as well as a white matter structure such as the corpus callosum (Narr et al., 2000). In addition, the cortical surface is also an object of the shape analysis in schizophrenia. Thompson and his colleagues demonstrated the usefulness of a shape analysis by applying various cortical surface analyses to MRI data (Thompson et al., 2004). In early onset schizophrenic patients, early deficits in parietal brain regions were found to anteriorly progress in the brain into the temporal lobes (Thompson et al., 2001). To our knowledge, however, a study investigating a cortical target structure instead of the whole brain has not been conducted until now. The insula is a good candidate for morphometric study because of its unique feature in the brain. It is a triangular-shaped cortical region, entirely enclosed and concealed within the sylvian fissure. Phylogenetically, the insula is an older portion of the telencephalon, and it connects with various cortical areas of the frontal, parietal and temporal lobes, limbic structures, including the amygdaloid body, as well as subcortical areas such as the caudate nucleus, putamen, claustrum, and dorsal thalamus (Ture et al., 1999). Although the comprehensive role of the insula continues to remain obscure, numerous clinical and experimental studies have indicated that it can be related to a variety of functions, such as memory, drive, higher autonomic control, gustation, and olfaction (Augustine, 1996). Therefore, the insula is increasingly the subject of great interest in psychiatric disorders of neurodevelopmental origin because of its anatomical location, wide interconnectivity, and variety of functions.
D.-P. Jang et al. / NeuroImage 32 (2006) 220 – 227
Volumetric abnormalities in the insula have been reported in some MR studies for schizophrenia. For example, volumetric reduction in the insula was identified in patients with first-episode schizophrenia (Crespo-Facorro et al., 2000) and chronic schizophrenia (Kim et al., 2003). This structural deficit in the insula was also demonstrated in a voxel-based morphometric study (Wright et al., 1999). However, a simple volume measurement would fail to reveal distinctive abnormality in the neurodevelopmental disorder despite the unique characteristics of the insula. On the other hand, if a special analyzing method is applied to the shape of the insula rather than the volume, such abnormality could be successfully visualized. This study was designed to investigate insular shape deformity in patients with schizophrenia. In this study, we suggested new analysis techniques using a 3D structural MRI to demonstrate the morphological characteristics of the insula. We hypothesized that the shape analysis of the insula would lead to unique structural deformity in the neurodevelopmental disorder, which cannot be revealed from a simple volume measurement.
Methods Subjects Subjects consisted of 23 patients (14 male and 9 female) with schizophrenia and 23 age- and sex-matched normal healthy controls (14 male and 9 female). The patients with schizophrenia were recruited from the inpatient unit at Severance Mental Health Hospital. The subjects fulfilled the DSM IV criteria (APA, 1994) for schizophrenia and had been diagnosed using the Structured Clinical Interview for DSM IV (First et al., 1996). Exclusion criteria were a lifetime history of neurological illnesses or a history of substance abuse. Control individuals were recruited from the community through newspaper advertisements and screened using the SCID-IV in order to exclude cases with current or lifetime history of a DSM IV axis I disorder. Mean ages were 24.4 (T3.6) and 24.3 (T3.6) in the patients with schizophrenia and the healthy controls, respectively. This study was carried out according to the guidelines for the use of human subjects established by the Institutional Review Board. After a complete description of the scope of the study to all subjects, written informed consent was obtained. Image acquisition and preprocessing MR scans of the entire brain were obtained using a 3.0-T General Electric SIGNA System (GE Medical Systems, Milwaukee, WI), with a 3D-SPGR T1-weighted spoiled gradient and echo pulse sequence with the following parameters: 1.0 mm coronal slices (192 slices); echo time = 1.28 ms; repetition time = 5.4 ms; number of excitations = 2; rotation angle = 20-; field of view = 22 22 cm; and a matrix of 512 512. The MR images were preprocessed using the image-processing software package, ANALYZE (version 6.0, Mayo Foundation, USA). Images were resampled to iso-voxels of 0.469 mm with the cubic-spline interpolation algorithm and spatially realigned so that the anterior – posterior axis of the brain was aligned parallel to the inter-commissural line and along the inter-hemispheric fissure, and the superior – inferior axis was also aligned along the interhemispheric fissure. The data sets were filtered using anisotropic
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diffusion methods with five iterations to improve the signal-tonoise ratio. Global volume measurement Tools from the FMRIB Software Library (FSL, http:// www.fmrib.ox.ac.uk/fsl) were used in order to extract the brain and tissue classification. T1-weighted MRI data were skull stripped (Smith, 2002), and the extracted brain images were segmented into gray matter, white matter, and cerebrospinal fluid (Zhang et al., 2001). The intracranial volume was calculated by adding the subtotal volume of the three tissue components. Insula tracing The insula was defined as a pyramid-shaped cortical area, enclosed by the superior circular insular sulcus, the inferior circular insular sulcus, and the orbitoinsular sulcus (Mesulam and Mufson, 1982; Ture et al., 1999). Tracing was performed manually on the drawing module of MRIcro (Chris Rorden, University of Nottingham, Great Britain). As shown in Fig. 1, a line of interest was drawn along the outer surface of the insula on all coronal slices that contained the insula. The anterior part of the insula in front of the limen insulae was defined as a cortical portion between the superior circular insular sulcus and the orbitoinsular sulcus. The rostral end of the insula was defined as the anteromost cortical area including the superior circular insular sulcus. The posterior part of the insula behind the limen insulae was defined as a cortical portion between the superior and inferior circular insular sulci. The caudal end of the insula was defined as the posterior-most cortical area including the two sulci within the fundus of the sylvian fissure. To assess the inter-rater reliability, tracing was performed independently on a set of 10 MR scans by two raters (DPJ and YCJ). The intraclass correlation coefficients for the right and left insular surface area were 0.89 and 0.91. Using this procedure, one rater (DPJ) traced the insula of all subjects. Structural analysis of the insula Three points of the anatomical landmarks for structural analysis were defined, as shown in Fig. 1. Since the insula was roughly a triangular shape, the anterior-most point was referred to as the rostral end of the insula (REI), the posterior-most point as the caudal end of the insula (CEI), and the most inferior point as the inferior limit of limen insulae (ILI). The measurement variables for structural analysis were the distances between these points, the angles of each point of the triangle, the shortest distances from each point into mid-hemisphere plane of the brain, and the area of the triangle. We used t tests to examine group difference on the angles of each point of the triangle. All measurements except those angle variables were subjected to an analysis of covariance (ANCOVA) for between-group differences, using the intracranial volume and age as a covariate. The significance level for all analyses was set at P < 0.05. Surface analysis of the insula In this study, we used an active, flexible, deformable surface model for analyzing the outer surface of the insula. The initial surface model was generated by subdividing the original triangle formed by the three anatomical landmarks REI, CEI and ILI, into
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Fig. 1. Schematic view of the manually traced outer surface of the insula (a) and outer surface tracing of the insula on the coronal view of T1-weighted image (b – g). Three anatomical insular landmarks were illustrated with different shaped makers; (b) the rostral end of the insula (REI); (e) the inferior limit of limen insulae (ILI); and (g) the caudal end of the insula (CEI).
256 polygons. The deformation process was performed with this initial 256 polygon model by minimizing an objective function, which was a weighted sum of three different forces: the Line of Interest (LOI) force (T LOI-dist), the LOI boundary force (T BOUNDdist), and the regularization force (T REGUL). An objective function was expressed as, OðS Þ ¼ w1 TLOIdist ðS Þ þ w2 TBOUNDdist ðS Þ þ w3 TREGUL ðS Þ where, S is the deforming surface model; w 1, w 2, and w 3 are the weighting factors for the LOI force, the LOI boundary force, and the regularization force, respectively. These weighting factors were empirically determined in this study. For the determination of weighting factors, 10 datasets were randomly tested by individually changing the weight factors for the LOI force (w 1) and LOI boundary force (w 2), while the weighting factor for the
regularization force (w 3). The average of distance between deforming surface model and traced LOI of the insula was evaluated with each of the various weight factor set. Finally, 0.01, 0.02, and 1 were used for w 1, w 2, and w 3 in this study, respectively. LOI force: The LOI force term presented here was based on the distance from a vertex on the deforming surface to the nearest LOI and was expressed as, nv
TLOIdist ¼
~ dLOI
x¯ v ;
v¼1
where n v is the number of vertices in a deforming surface mesh; x¯ v = (x v, y v, z v ) is 3D position of vertex v; and d LOI(x¯ v ) is the Euclidian distance to the nearest LOI from a vertex v on the deforming surface.
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LOI boundary force: The LOI boundary force was defined as the distance the deforming surface boundary moves toward the boundary of LOI while preventing shrinkage of the deforming surface. nB
TBOUND dist ¼
~ dBOUND
x¯ B ;
B¼1
where x¯ B = (x B , y B , z B ) is the 3D position of boundary vertex B in a surface mesh, which has four neighbor vertices; n B is the number of boundary vertices in a surface mesh; and d BOUND(x¯ B ) is the Euclidian distance from a boundary vertex B on the deforming surface into the nearest LOI boundary, which is defined as the two end points of the LOI in the coronal image shown as a white boundary dot in Fig. 2. LOI and LOI boundary terms were based on the minimum distance field. After the tracing of insula LOI, a distance map was made by assigning a distance from the insula to each voxel. This information was then utilized during the deformation process as data driven external force. Regularization force: For the smooth deforming surface, the regularization force was defined and expressed as, x¯ ðM ;vÞ ¼
1 nN
nN
~ x¯ ðN ;vÞ
N ¼1
nv
TREGUL ¼
~ jx¯ v x¯ ðM;vÞ j
v¼1
where x¯ (N,v) is the 3D position of neighbor vertices of the current vertex v; n N is the number of v’s neighbor vertices; and x¯ (M,v) is the mean position of all vertices neighboring the current vertex. This was used to find the difference vector (x¯ v x¯ (M,v)), which updated the position of the current vertex toward the mean position of its neighbors. If this vector was minimized for all vertices, the surface would be smoothed by default, and all vertices would be equally
Fig. 3. Sagittal, coronal, and axial sections of the deformed surface (red line) superimposed on a voxel map of the traced outer surface of the insula (white line).
spaced. However, this regularization force could cause the surface model not to follow the insular gyri due to the smoothness constraint. Powell’s multidimensional direction set method was used to minimize the objective function (Press et al., 1992). The difference between current objective function and previous objective function
Fig. 2. Overview of the insular surface analysis. The initial surface model was generated by subdividing the original triangle formed by the three anatomical landmarks into four triangles until 256 triangles were achieved. The 256 triangle area was then deformed to fit data from the line of interest (LOI). The deformed polygonal surface was resampled to contain 1024 polygons, and the deformation process was repeated.
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Table 1 Mean [SD] values for global volume measurements and the surface area of the parameterized insular outer surface
Global volume (cc)
Insular surface (cm2)
Cerebrospinal fluid Gray matter White matter Intracranial volume Right Left
Schizophrenia (N = 23)
Normal control (N = 23)
P
329 [49] 709 [64] 453 [36] 1491 [127] 56.6 [6.2] 58.8 [5.7]
309 [52] 719 [69] 473 [51] 1501 [149] 57.1 [3.6] 58.4 [4.5]
N.S. N.S. N.S. N.S. N.S. N.S.
N.S., not significant.
was used as a convergence criterion (<0.01). When minimizing the objective function, three anatomical landmark vertices (REI, CEI, and ILI) were excluded in the deformation process as anatomical corresponding points between subjects. In order to increase the chances of finding the global minimum, a multiscale approach was employed. Deformation began with the initial low-resolution (256 polygons) triangle surface model. The low-resolution surface was deformed to fit the LOI image data. The deformed polygonal surface was then resampled to contain more polygons (1024 polygons), and the deformation process was repeated, as illustrated in Fig. 2. Parameterized insular surface models were obtained for each LOI data set in all subject groups by the same algorithm. Evaluation of the parameterized surface model was performed by superimposing the deformed surface on voxel data from the insular LOIs, as shown in Fig. 3. The insular surfaces of the LOI were parameterized by excluding three anatomical landmark vertices (REI, CEI, and ILI) in the deformation process, providing a point-to-point correspondence between homologous surface points. In order to increase the signal-to-noise ratio (Dougherty, 1999), we applied diffusion smoothing to the insular surface with a 6-mm full width at half maximum diffusion Gaussian kernel for 200 iterations (Chung et al., 2003). The shape difference between the patient group and the healthy control group was estimated using the
shortest distance from the points of the deformed surface to the plane containing the initial triangle. Significant differences in all homologous surface points were evaluated using two-tailed Student’s t tests and mapped on the individual insular surface data. Multiple comparisons were controlled for by adjusting the T threshold using the false discovery rate (FDR) procedure ( P < 0.05 FDR corrected threshold) (Genovese et al., 2002).
Results Comparison of global measurements As shown in Table 1, significant group difference between the patients with schizophrenia and the healthy controls was not found in all global volume measurements, including gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and intracranial volume (ICV). Comparison of structural measurements in the insula Structural measurements from the three anatomical landmarks are listed in Table 2. Based on the finding that the area of the anatomical landmark triangle of the insula was significantly
Table 2 Structural measurements of the triangle of three insular anatomical landmarks
Left
Right
Variable
Schizophrenia
Normal control
Statistics
Mean
SD
Mean
SD
F
Distance from REIa to CEIb Distance from REI to ILIc Distance from ILI to CEI REI angle ILI angle CEI angle Distance from REI to inter-hemisphere Distance from ILI to inter-hemisphere Distance from CEI to inter-hemisphere Area of triangle Distance from REI to CEI Distance from REI to ILI Distance from ILI to CEI REI angle ILI angle CEI angle Distance from REI to inter-hemisphere Distance from ILI to inter-hemisphere Distance from CEI to inter-hemisphere Area of triangle
54.4 32.5 46.7 58.3 85.2 36.6 71.0 85.7 65.2 34.9 53.4 30.1 46.7 60.4 85.3 34.3 67.4 80.2 63.1 32.6
4.3 2.7 2.4 4.1 8.4 5.2 4.4 4.3 3.7 4.0 3.0 3.3 2.6 3.7 5.7 4.4 3.8 6.0 4.4 4.7
54.7 32.7 47.3 59.2 84.3 36.5 71.1 85.7 65.0 34.8 53.3 32.0 47.5 61.7 82.0 36.3 67.5 78.7 63.6 34.1
2.9 2.9 2.5 4.2 6.0 4.2 4.9 4.9 5.1 3.4 2.6 2.8 3.4 4.6 5.7 3.7 4.4 4.3 5.9 3.9
N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. <.05 N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S.
Keys: athe rostral end of the insula (REI), bthe caudal end of the insula (CEI). cthe inferior limit of limen insulae (ILI). N.S., not significant. Unit of measurement is millimeter for distance, degree for angle, and centimeter squared for area.
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correlated with ICV (right: r = 0.442, P < 0.001; left: r = 0.523, P < 0.0001) and age (right: r = 0.425, P < 0.01; left: r = 0.357, P < 0.01), structural analyses of insula differences between the two groups were carried out using ICV and age as a covariate. On the right side, the patients with schizophrenia (30.1 mm, SD = 3.3) had significantly shorter REI to ILI length than the healthy controls (32.0 mm, SD = 2.8) ( F = 4.10, P < 0.05). Any other variables including the triangular area of the right insula were not significantly different between the two groups. On the other hand, there was no significantly different variable on the left insula. Deformity of the insular outer surface As shown in Table 1, no significant group difference in the total parameterized insular surface areas was found in both sides. However, Fig. 4 shows that there are deformity patterns of the insular outer surface in the patients with schizophrenia. The redcolored polygons indicate significant decreases in the distances from the points of the deformed surface to the plane of the initial triangle. Deformation found in the patients resulted only from decreases in distance, without any significant increases. Characteristically, deformed regions were found in the frontal and
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temporal sides of the right insula, whereas deformation in the left insula was minimal.
Discussion In the current study, the length between REI and ILI in the right insula was decreased in the patients with schizophrenia. It is noteworthy that these two landmarks, REI and ILI, are located on the border of the frontal and temporal lobes, respectively. In addition, partial regions in the frontal and temporal sides of the right insula were significantly deformed in the patients with schizophrenia, as shown in Fig. 4. It is not clear if this deformation in the right insula is associated with insular dysfunction. Various functional imaging studies have shown decreased function of the insular cortex in patients with schizophrenia (Curtis et al., 1998; Kim et al., 2000). It is very interesting that the directions of these two abnormal sides correspond to results from lots of functional imaging studies, which have reported that information processing subserved by frontotemporal interactions is impaired during various task conditions in patients with schizophrenia (Mann et al., 1997; Jennings et al., 1998; Fletcher et al., 1999; Spence et al.,
Fig. 4. The deformity pattern of the insular outer surface in schizophrenia. The shortest distance from the points of deformed surface to the plane of the initial triangle was measured. The deformity areas were displayed where the distances in the patient group were significantly decreased compared with those of the healthy controls.
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2000; Josin and Liddle, 2001; Meyer-Lindenberg et al., 2001; Lawrie et al., 2002; Welchew et al., 2002; Winterer et al., 2003). Deformation in the frontotemporal sides of the insula may be an extension of subtle structural abnormalities of the frontal and temporal lobes underlying these dysfunctions. Based on the physical tension mechanism of brain shape deformation, it seems that there is an abnormal physical tension of brain growth during neurodevelopment in the patients with schizophrenia, particularly in the frontal and temporal lobes of the right hemisphere, which may lead to the right insular deformation. It has been suggested that there are some pathological processes including a reduction in interneuronal neuropil in the frontotemporal regions (Selemon and Goldman-Rakic, 1999). It is also possible that insular deformation of the frontotemporal sides in the current study may reflect abnormalities in the underlying frontotemporal white matter tact organization. Corticocortical interconnections in schizophrenia can be disrupted due to abnormal neurodevelopmental organization of the white matter tract such as displaced interstitial neurons and aberrant myelination (Lim et al., 1999). This abnormal neurodevelopment can be associated with the frontotemporal disconnectivity in schizophrenia. A pattern showing disturbed frontotemporal interactions was suggested as a trait marker (Meyer-Lindenberg et al., 2001). However, it should be noted that our results cannot be direct evidence of the disturbed frontotemporal interactions in schizophrenia as the main frontotemporal connection is the uncinate fasciculus which is apart from the insula. It is noteworthy that deformation of the insula was observed only in the right side. In fact, although a volumetric reduction of the insula has been reported in patients with schizophrenia, impairment was found bilaterally (Goldstein et al., 1999; Wright et al., 1999) or in the left side (Crespo-Facorro et al., 2000; Kim et al., 2003). It should be noted that the deformation found in the shape analysis is different from the volumetric GM deficits. The structural deformity and the GM volume change may be induced by different mechanisms. The mechanical meaning of the surface deformity in the current study was that the insular surface was changed to the direction of anatomical landmark surface. Given that there was no difference in the parameterized insular surface area between the patients with schizophrenia and the normal controls, insular surface deformations can stem from focal reductions in cortical thickness. Because GM volumes of the insula were not measured in this study, it is uncertain whether there is GM deficit in the right insula due to a reduction in cortical thickness without a reduction in surface area. It should be considered, however, that a simple reduction in insular cortical thickness cannot make the length between the landmarks such as REI and ILI to be decreased. Therefore, abnormalities in the right insula could be induced by subtle mechanical changes in structures around the insula rather than by a GM volume reduction. It could be possible due to the central position of the insula facing the frontal, temporal, and parietal lobes. Shape deformation may be associated with the physical properties of morphogenetic mechanisms that directly impact the particular shape of brain regions during neurodevelopment (Van Essen, 1997; Van Essen and Drury, 1997). One of important technical factors to be carefully treated in the shape analysis is the parameterization, providing a point-to-point correspondence between the homologous surface points in a group. Landmark based morphometrics have been the first attempt to obtain representation of shape (Bookstein, 1996). The landmark
feature was suitable for have the distinct point such as anterior – posterior commissure and the major sulci. In this study, we parameterized the surface model with three anatomical landmarks REI, CEI, and ILI, since the insula was roughly a triangular shape and each end points of the triangle could be landmark. By excluding those landmark vertices in the deformation process of insular surface model, we tried to preserve the correspondence and topology between the vertices of surface models in a group. However, since the performance of this approach depends on the accuracy of manually placed landmarks, there could be intra- and inter-rater variabilities and reliabilities. In this study, the characteristic of our parameterization method was not systematically evaluated. Thus, the parameterization based on triangular anatomical shape should be evaluated in the further study for robust insula shape analysis. Our study showed that a deformation of the insula could be demonstrated by a special shape analysis technique. In general, a GM deficit in schizophrenia tended to be too subtle to be observed by sight. The shape analysis can be a powerful tool for uncovering subtle structural changes in schizophrenia. Based on the neurodevelopmental hypothesis of schizophrenia (Bloom, 1993; Weinberger, 1995), the insular deformation in the patients with schizophrenia may develop in an early stage of life. In summary, we introduced a landmark-based structural and surface shape analysis of the insula in order to demonstrate a subtle change of the neurodevelopmental origin in schizophrenia. The characteristic finding was that the frontotemporal sides of the right insula were deformed in the patients with schizophrenia. This deformation can be associated with frontotemporal abnormalities in schizophrenia. Although additional studies are needed to elucidate the base of the structural deformation, the results from this study may provide a new insight into the patterns of abnormal neurodevelopment in schizophrenia.
Acknowledgments This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A040042), and the Korea Science and Engineering Foundation, interdisciplinary research (Contract grant number: R01-2002-00000362-0).
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Shape deformation of the insula in schizophrenia Dong-Pyo Jang,a,e Jae-Jin Kim,b,c,d,* Tae-Sub Chung,d Suk Kyoon An,b,c Young Chul Jung,b,c Jun-Kee Lee,a Jong-Min Lee,a In-Young Kim,a and Sun I. Kim a a
Department of Biomedical Engineering, Hanyang University, Seoul, Korea Department of Psychiatry, Yonsei University College of Medicine, Seoul, Korea c Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Korea d Department of Diagnostic Radiology, Yonsei University College of Medicine, Seoul, Korea e Neuroscience Research Institute, Gachon Medical School, Seoul, Korea b
Received 29 October 2005; revised 22 December 2005; accepted 25 January 2006 Available online 26 May 2006 Schizophrenia has been conceptualized to be a neurodevelopmental disorder. Neuroimaging evidence was generally findings of volumetric reductions in various brain structures. The shape analysis of the insula can uncover unique structural deformity in the neurodevelopmental disorder, which cannot be revealed from a simple volume measurement. The objective of this study was to demonstrate a subtle change of the insula in schizophrenia using our special shape analysis technique. Subjects were 23 patients with schizophrenia and 23 normal healthy subjects. A landmark-based structural and surface shape analysis of the insula was performed using high-spatial resolution magnetic resonance imaging. A characteristic finding was that the frontotemporal sides of the right insula were deformed in the patients with schizophrenia compared with normal controls. This deformation can be associated with abnormal development of the frontal and temporal lobes in schizophrenia. D 2006 Elsevier Inc. All rights reserved. Keywords: Schizophrenia; Insula; MRI; Shape analysis
Introduction Schizophrenia is a devastating mental illness that usually produces chronic disability for affected individuals. It has been conceptualized that the pathogenesis of schizophrenia may be neurodevelopmental in nature (Bloom, 1993; Weinberger, 1995). As suggested by the term Fneurodevelopment_, the structural abnormalities of brain volume observed in schizophrenia could be influenced by intrauterine, perinatal, and extrauterine insults, as well as neurobiological maturational processes. Magnetic resonance (MR) studies have demonstrated volume reductions in
* Corresponding author. Department of Psychiatry, Yonsei University College of Medicine, Severance Mental Health Hospital, 696-6 Tanbuldong Gwangju-si, Geonggi-do 464-100, Korea. Fax: +82 31 761 7582. E-mail address: [email protected] (J.-J. Kim). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.01.032
various brain structures in schizophrenia (Shenton et al., 2001). However, simple MR volumetric reductions are not enough to be evidence of the neurodevelopmental abnormality because they are also observed in neurodegenerative cortical atrophy. More advanced morphometric tools are needed in order to elucidate structural deformities derived from the abnormal neurodevelopmental processes. A shape analysis is an example of such a study. Abnormal brain morphology in schizophrenia has been demonstrated in a subcortical structure such as the hippocampus (Shenton et al., 2002; Lee et al., 2004) as well as a white matter structure such as the corpus callosum (Narr et al., 2000). In addition, the cortical surface is also an object of the shape analysis in schizophrenia. Thompson and his colleagues demonstrated the usefulness of a shape analysis by applying various cortical surface analyses to MRI data (Thompson et al., 2004). In early onset schizophrenic patients, early deficits in parietal brain regions were found to anteriorly progress in the brain into the temporal lobes (Thompson et al., 2001). To our knowledge, however, a study investigating a cortical target structure instead of the whole brain has not been conducted until now. The insula is a good candidate for morphometric study because of its unique feature in the brain. It is a triangular-shaped cortical region, entirely enclosed and concealed within the sylvian fissure. Phylogenetically, the insula is an older portion of the telencephalon, and it connects with various cortical areas of the frontal, parietal and temporal lobes, limbic structures, including the amygdaloid body, as well as subcortical areas such as the caudate nucleus, putamen, claustrum, and dorsal thalamus (Ture et al., 1999). Although the comprehensive role of the insula continues to remain obscure, numerous clinical and experimental studies have indicated that it can be related to a variety of functions, such as memory, drive, higher autonomic control, gustation, and olfaction (Augustine, 1996). Therefore, the insula is increasingly the subject of great interest in psychiatric disorders of neurodevelopmental origin because of its anatomical location, wide interconnectivity, and variety of functions.
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Volumetric abnormalities in the insula have been reported in some MR studies for schizophrenia. For example, volumetric reduction in the insula was identified in patients with first-episode schizophrenia (Crespo-Facorro et al., 2000) and chronic schizophrenia (Kim et al., 2003). This structural deficit in the insula was also demonstrated in a voxel-based morphometric study (Wright et al., 1999). However, a simple volume measurement would fail to reveal distinctive abnormality in the neurodevelopmental disorder despite the unique characteristics of the insula. On the other hand, if a special analyzing method is applied to the shape of the insula rather than the volume, such abnormality could be successfully visualized. This study was designed to investigate insular shape deformity in patients with schizophrenia. In this study, we suggested new analysis techniques using a 3D structural MRI to demonstrate the morphological characteristics of the insula. We hypothesized that the shape analysis of the insula would lead to unique structural deformity in the neurodevelopmental disorder, which cannot be revealed from a simple volume measurement.
Methods Subjects Subjects consisted of 23 patients (14 male and 9 female) with schizophrenia and 23 age- and sex-matched normal healthy controls (14 male and 9 female). The patients with schizophrenia were recruited from the inpatient unit at Severance Mental Health Hospital. The subjects fulfilled the DSM IV criteria (APA, 1994) for schizophrenia and had been diagnosed using the Structured Clinical Interview for DSM IV (First et al., 1996). Exclusion criteria were a lifetime history of neurological illnesses or a history of substance abuse. Control individuals were recruited from the community through newspaper advertisements and screened using the SCID-IV in order to exclude cases with current or lifetime history of a DSM IV axis I disorder. Mean ages were 24.4 (T3.6) and 24.3 (T3.6) in the patients with schizophrenia and the healthy controls, respectively. This study was carried out according to the guidelines for the use of human subjects established by the Institutional Review Board. After a complete description of the scope of the study to all subjects, written informed consent was obtained. Image acquisition and preprocessing MR scans of the entire brain were obtained using a 3.0-T General Electric SIGNA System (GE Medical Systems, Milwaukee, WI), with a 3D-SPGR T1-weighted spoiled gradient and echo pulse sequence with the following parameters: 1.0 mm coronal slices (192 slices); echo time = 1.28 ms; repetition time = 5.4 ms; number of excitations = 2; rotation angle = 20-; field of view = 22 22 cm; and a matrix of 512 512. The MR images were preprocessed using the image-processing software package, ANALYZE (version 6.0, Mayo Foundation, USA). Images were resampled to iso-voxels of 0.469 mm with the cubic-spline interpolation algorithm and spatially realigned so that the anterior – posterior axis of the brain was aligned parallel to the inter-commissural line and along the inter-hemispheric fissure, and the superior – inferior axis was also aligned along the interhemispheric fissure. The data sets were filtered using anisotropic
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diffusion methods with five iterations to improve the signal-tonoise ratio. Global volume measurement Tools from the FMRIB Software Library (FSL, http:// www.fmrib.ox.ac.uk/fsl) were used in order to extract the brain and tissue classification. T1-weighted MRI data were skull stripped (Smith, 2002), and the extracted brain images were segmented into gray matter, white matter, and cerebrospinal fluid (Zhang et al., 2001). The intracranial volume was calculated by adding the subtotal volume of the three tissue components. Insula tracing The insula was defined as a pyramid-shaped cortical area, enclosed by the superior circular insular sulcus, the inferior circular insular sulcus, and the orbitoinsular sulcus (Mesulam and Mufson, 1982; Ture et al., 1999). Tracing was performed manually on the drawing module of MRIcro (Chris Rorden, University of Nottingham, Great Britain). As shown in Fig. 1, a line of interest was drawn along the outer surface of the insula on all coronal slices that contained the insula. The anterior part of the insula in front of the limen insulae was defined as a cortical portion between the superior circular insular sulcus and the orbitoinsular sulcus. The rostral end of the insula was defined as the anteromost cortical area including the superior circular insular sulcus. The posterior part of the insula behind the limen insulae was defined as a cortical portion between the superior and inferior circular insular sulci. The caudal end of the insula was defined as the posterior-most cortical area including the two sulci within the fundus of the sylvian fissure. To assess the inter-rater reliability, tracing was performed independently on a set of 10 MR scans by two raters (DPJ and YCJ). The intraclass correlation coefficients for the right and left insular surface area were 0.89 and 0.91. Using this procedure, one rater (DPJ) traced the insula of all subjects. Structural analysis of the insula Three points of the anatomical landmarks for structural analysis were defined, as shown in Fig. 1. Since the insula was roughly a triangular shape, the anterior-most point was referred to as the rostral end of the insula (REI), the posterior-most point as the caudal end of the insula (CEI), and the most inferior point as the inferior limit of limen insulae (ILI). The measurement variables for structural analysis were the distances between these points, the angles of each point of the triangle, the shortest distances from each point into mid-hemisphere plane of the brain, and the area of the triangle. We used t tests to examine group difference on the angles of each point of the triangle. All measurements except those angle variables were subjected to an analysis of covariance (ANCOVA) for between-group differences, using the intracranial volume and age as a covariate. The significance level for all analyses was set at P < 0.05. Surface analysis of the insula In this study, we used an active, flexible, deformable surface model for analyzing the outer surface of the insula. The initial surface model was generated by subdividing the original triangle formed by the three anatomical landmarks REI, CEI and ILI, into
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Fig. 1. Schematic view of the manually traced outer surface of the insula (a) and outer surface tracing of the insula on the coronal view of T1-weighted image (b – g). Three anatomical insular landmarks were illustrated with different shaped makers; (b) the rostral end of the insula (REI); (e) the inferior limit of limen insulae (ILI); and (g) the caudal end of the insula (CEI).
256 polygons. The deformation process was performed with this initial 256 polygon model by minimizing an objective function, which was a weighted sum of three different forces: the Line of Interest (LOI) force (T LOI-dist), the LOI boundary force (T BOUNDdist), and the regularization force (T REGUL). An objective function was expressed as, OðS Þ ¼ w1 TLOIdist ðS Þ þ w2 TBOUNDdist ðS Þ þ w3 TREGUL ðS Þ where, S is the deforming surface model; w 1, w 2, and w 3 are the weighting factors for the LOI force, the LOI boundary force, and the regularization force, respectively. These weighting factors were empirically determined in this study. For the determination of weighting factors, 10 datasets were randomly tested by individually changing the weight factors for the LOI force (w 1) and LOI boundary force (w 2), while the weighting factor for the
regularization force (w 3). The average of distance between deforming surface model and traced LOI of the insula was evaluated with each of the various weight factor set. Finally, 0.01, 0.02, and 1 were used for w 1, w 2, and w 3 in this study, respectively. LOI force: The LOI force term presented here was based on the distance from a vertex on the deforming surface to the nearest LOI and was expressed as, nv
TLOIdist ¼
~ dLOI
x¯ v ;
v¼1
where n v is the number of vertices in a deforming surface mesh; x¯ v = (x v, y v, z v ) is 3D position of vertex v; and d LOI(x¯ v ) is the Euclidian distance to the nearest LOI from a vertex v on the deforming surface.
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LOI boundary force: The LOI boundary force was defined as the distance the deforming surface boundary moves toward the boundary of LOI while preventing shrinkage of the deforming surface. nB
TBOUND dist ¼
~ dBOUND
x¯ B ;
B¼1
where x¯ B = (x B , y B , z B ) is the 3D position of boundary vertex B in a surface mesh, which has four neighbor vertices; n B is the number of boundary vertices in a surface mesh; and d BOUND(x¯ B ) is the Euclidian distance from a boundary vertex B on the deforming surface into the nearest LOI boundary, which is defined as the two end points of the LOI in the coronal image shown as a white boundary dot in Fig. 2. LOI and LOI boundary terms were based on the minimum distance field. After the tracing of insula LOI, a distance map was made by assigning a distance from the insula to each voxel. This information was then utilized during the deformation process as data driven external force. Regularization force: For the smooth deforming surface, the regularization force was defined and expressed as, x¯ ðM ;vÞ ¼
1 nN
nN
~ x¯ ðN ;vÞ
N ¼1
nv
TREGUL ¼
~ jx¯ v x¯ ðM;vÞ j
v¼1
where x¯ (N,v) is the 3D position of neighbor vertices of the current vertex v; n N is the number of v’s neighbor vertices; and x¯ (M,v) is the mean position of all vertices neighboring the current vertex. This was used to find the difference vector (x¯ v x¯ (M,v)), which updated the position of the current vertex toward the mean position of its neighbors. If this vector was minimized for all vertices, the surface would be smoothed by default, and all vertices would be equally
Fig. 3. Sagittal, coronal, and axial sections of the deformed surface (red line) superimposed on a voxel map of the traced outer surface of the insula (white line).
spaced. However, this regularization force could cause the surface model not to follow the insular gyri due to the smoothness constraint. Powell’s multidimensional direction set method was used to minimize the objective function (Press et al., 1992). The difference between current objective function and previous objective function
Fig. 2. Overview of the insular surface analysis. The initial surface model was generated by subdividing the original triangle formed by the three anatomical landmarks into four triangles until 256 triangles were achieved. The 256 triangle area was then deformed to fit data from the line of interest (LOI). The deformed polygonal surface was resampled to contain 1024 polygons, and the deformation process was repeated.
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Table 1 Mean [SD] values for global volume measurements and the surface area of the parameterized insular outer surface
Global volume (cc)
Insular surface (cm2)
Cerebrospinal fluid Gray matter White matter Intracranial volume Right Left
Schizophrenia (N = 23)
Normal control (N = 23)
P
329 [49] 709 [64] 453 [36] 1491 [127] 56.6 [6.2] 58.8 [5.7]
309 [52] 719 [69] 473 [51] 1501 [149] 57.1 [3.6] 58.4 [4.5]
N.S. N.S. N.S. N.S. N.S. N.S.
N.S., not significant.
was used as a convergence criterion (<0.01). When minimizing the objective function, three anatomical landmark vertices (REI, CEI, and ILI) were excluded in the deformation process as anatomical corresponding points between subjects. In order to increase the chances of finding the global minimum, a multiscale approach was employed. Deformation began with the initial low-resolution (256 polygons) triangle surface model. The low-resolution surface was deformed to fit the LOI image data. The deformed polygonal surface was then resampled to contain more polygons (1024 polygons), and the deformation process was repeated, as illustrated in Fig. 2. Parameterized insular surface models were obtained for each LOI data set in all subject groups by the same algorithm. Evaluation of the parameterized surface model was performed by superimposing the deformed surface on voxel data from the insular LOIs, as shown in Fig. 3. The insular surfaces of the LOI were parameterized by excluding three anatomical landmark vertices (REI, CEI, and ILI) in the deformation process, providing a point-to-point correspondence between homologous surface points. In order to increase the signal-to-noise ratio (Dougherty, 1999), we applied diffusion smoothing to the insular surface with a 6-mm full width at half maximum diffusion Gaussian kernel for 200 iterations (Chung et al., 2003). The shape difference between the patient group and the healthy control group was estimated using the
shortest distance from the points of the deformed surface to the plane containing the initial triangle. Significant differences in all homologous surface points were evaluated using two-tailed Student’s t tests and mapped on the individual insular surface data. Multiple comparisons were controlled for by adjusting the T threshold using the false discovery rate (FDR) procedure ( P < 0.05 FDR corrected threshold) (Genovese et al., 2002).
Results Comparison of global measurements As shown in Table 1, significant group difference between the patients with schizophrenia and the healthy controls was not found in all global volume measurements, including gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and intracranial volume (ICV). Comparison of structural measurements in the insula Structural measurements from the three anatomical landmarks are listed in Table 2. Based on the finding that the area of the anatomical landmark triangle of the insula was significantly
Table 2 Structural measurements of the triangle of three insular anatomical landmarks
Left
Right
Variable
Schizophrenia
Normal control
Statistics
Mean
SD
Mean
SD
F
Distance from REIa to CEIb Distance from REI to ILIc Distance from ILI to CEI REI angle ILI angle CEI angle Distance from REI to inter-hemisphere Distance from ILI to inter-hemisphere Distance from CEI to inter-hemisphere Area of triangle Distance from REI to CEI Distance from REI to ILI Distance from ILI to CEI REI angle ILI angle CEI angle Distance from REI to inter-hemisphere Distance from ILI to inter-hemisphere Distance from CEI to inter-hemisphere Area of triangle
54.4 32.5 46.7 58.3 85.2 36.6 71.0 85.7 65.2 34.9 53.4 30.1 46.7 60.4 85.3 34.3 67.4 80.2 63.1 32.6
4.3 2.7 2.4 4.1 8.4 5.2 4.4 4.3 3.7 4.0 3.0 3.3 2.6 3.7 5.7 4.4 3.8 6.0 4.4 4.7
54.7 32.7 47.3 59.2 84.3 36.5 71.1 85.7 65.0 34.8 53.3 32.0 47.5 61.7 82.0 36.3 67.5 78.7 63.6 34.1
2.9 2.9 2.5 4.2 6.0 4.2 4.9 4.9 5.1 3.4 2.6 2.8 3.4 4.6 5.7 3.7 4.4 4.3 5.9 3.9
N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. <.05 N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S.
Keys: athe rostral end of the insula (REI), bthe caudal end of the insula (CEI). cthe inferior limit of limen insulae (ILI). N.S., not significant. Unit of measurement is millimeter for distance, degree for angle, and centimeter squared for area.
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correlated with ICV (right: r = 0.442, P < 0.001; left: r = 0.523, P < 0.0001) and age (right: r = 0.425, P < 0.01; left: r = 0.357, P < 0.01), structural analyses of insula differences between the two groups were carried out using ICV and age as a covariate. On the right side, the patients with schizophrenia (30.1 mm, SD = 3.3) had significantly shorter REI to ILI length than the healthy controls (32.0 mm, SD = 2.8) ( F = 4.10, P < 0.05). Any other variables including the triangular area of the right insula were not significantly different between the two groups. On the other hand, there was no significantly different variable on the left insula. Deformity of the insular outer surface As shown in Table 1, no significant group difference in the total parameterized insular surface areas was found in both sides. However, Fig. 4 shows that there are deformity patterns of the insular outer surface in the patients with schizophrenia. The redcolored polygons indicate significant decreases in the distances from the points of the deformed surface to the plane of the initial triangle. Deformation found in the patients resulted only from decreases in distance, without any significant increases. Characteristically, deformed regions were found in the frontal and
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temporal sides of the right insula, whereas deformation in the left insula was minimal.
Discussion In the current study, the length between REI and ILI in the right insula was decreased in the patients with schizophrenia. It is noteworthy that these two landmarks, REI and ILI, are located on the border of the frontal and temporal lobes, respectively. In addition, partial regions in the frontal and temporal sides of the right insula were significantly deformed in the patients with schizophrenia, as shown in Fig. 4. It is not clear if this deformation in the right insula is associated with insular dysfunction. Various functional imaging studies have shown decreased function of the insular cortex in patients with schizophrenia (Curtis et al., 1998; Kim et al., 2000). It is very interesting that the directions of these two abnormal sides correspond to results from lots of functional imaging studies, which have reported that information processing subserved by frontotemporal interactions is impaired during various task conditions in patients with schizophrenia (Mann et al., 1997; Jennings et al., 1998; Fletcher et al., 1999; Spence et al.,
Fig. 4. The deformity pattern of the insular outer surface in schizophrenia. The shortest distance from the points of deformed surface to the plane of the initial triangle was measured. The deformity areas were displayed where the distances in the patient group were significantly decreased compared with those of the healthy controls.
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2000; Josin and Liddle, 2001; Meyer-Lindenberg et al., 2001; Lawrie et al., 2002; Welchew et al., 2002; Winterer et al., 2003). Deformation in the frontotemporal sides of the insula may be an extension of subtle structural abnormalities of the frontal and temporal lobes underlying these dysfunctions. Based on the physical tension mechanism of brain shape deformation, it seems that there is an abnormal physical tension of brain growth during neurodevelopment in the patients with schizophrenia, particularly in the frontal and temporal lobes of the right hemisphere, which may lead to the right insular deformation. It has been suggested that there are some pathological processes including a reduction in interneuronal neuropil in the frontotemporal regions (Selemon and Goldman-Rakic, 1999). It is also possible that insular deformation of the frontotemporal sides in the current study may reflect abnormalities in the underlying frontotemporal white matter tact organization. Corticocortical interconnections in schizophrenia can be disrupted due to abnormal neurodevelopmental organization of the white matter tract such as displaced interstitial neurons and aberrant myelination (Lim et al., 1999). This abnormal neurodevelopment can be associated with the frontotemporal disconnectivity in schizophrenia. A pattern showing disturbed frontotemporal interactions was suggested as a trait marker (Meyer-Lindenberg et al., 2001). However, it should be noted that our results cannot be direct evidence of the disturbed frontotemporal interactions in schizophrenia as the main frontotemporal connection is the uncinate fasciculus which is apart from the insula. It is noteworthy that deformation of the insula was observed only in the right side. In fact, although a volumetric reduction of the insula has been reported in patients with schizophrenia, impairment was found bilaterally (Goldstein et al., 1999; Wright et al., 1999) or in the left side (Crespo-Facorro et al., 2000; Kim et al., 2003). It should be noted that the deformation found in the shape analysis is different from the volumetric GM deficits. The structural deformity and the GM volume change may be induced by different mechanisms. The mechanical meaning of the surface deformity in the current study was that the insular surface was changed to the direction of anatomical landmark surface. Given that there was no difference in the parameterized insular surface area between the patients with schizophrenia and the normal controls, insular surface deformations can stem from focal reductions in cortical thickness. Because GM volumes of the insula were not measured in this study, it is uncertain whether there is GM deficit in the right insula due to a reduction in cortical thickness without a reduction in surface area. It should be considered, however, that a simple reduction in insular cortical thickness cannot make the length between the landmarks such as REI and ILI to be decreased. Therefore, abnormalities in the right insula could be induced by subtle mechanical changes in structures around the insula rather than by a GM volume reduction. It could be possible due to the central position of the insula facing the frontal, temporal, and parietal lobes. Shape deformation may be associated with the physical properties of morphogenetic mechanisms that directly impact the particular shape of brain regions during neurodevelopment (Van Essen, 1997; Van Essen and Drury, 1997). One of important technical factors to be carefully treated in the shape analysis is the parameterization, providing a point-to-point correspondence between the homologous surface points in a group. Landmark based morphometrics have been the first attempt to obtain representation of shape (Bookstein, 1996). The landmark
feature was suitable for have the distinct point such as anterior – posterior commissure and the major sulci. In this study, we parameterized the surface model with three anatomical landmarks REI, CEI, and ILI, since the insula was roughly a triangular shape and each end points of the triangle could be landmark. By excluding those landmark vertices in the deformation process of insular surface model, we tried to preserve the correspondence and topology between the vertices of surface models in a group. However, since the performance of this approach depends on the accuracy of manually placed landmarks, there could be intra- and inter-rater variabilities and reliabilities. In this study, the characteristic of our parameterization method was not systematically evaluated. Thus, the parameterization based on triangular anatomical shape should be evaluated in the further study for robust insula shape analysis. Our study showed that a deformation of the insula could be demonstrated by a special shape analysis technique. In general, a GM deficit in schizophrenia tended to be too subtle to be observed by sight. The shape analysis can be a powerful tool for uncovering subtle structural changes in schizophrenia. Based on the neurodevelopmental hypothesis of schizophrenia (Bloom, 1993; Weinberger, 1995), the insular deformation in the patients with schizophrenia may develop in an early stage of life. In summary, we introduced a landmark-based structural and surface shape analysis of the insula in order to demonstrate a subtle change of the neurodevelopmental origin in schizophrenia. The characteristic finding was that the frontotemporal sides of the right insula were deformed in the patients with schizophrenia. This deformation can be associated with frontotemporal abnormalities in schizophrenia. Although additional studies are needed to elucidate the base of the structural deformation, the results from this study may provide a new insight into the patterns of abnormal neurodevelopment in schizophrenia.
Acknowledgments This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A040042), and the Korea Science and Engineering Foundation, interdisciplinary research (Contract grant number: R01-2002-00000362-0).
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