Ventricular shape of monozygotic twins discordant for schizophrenia reflects vulnerability 2 M Styner, 1,2 G Gerig, 3 DW Jones, 3 DR Weinberger, 1 JA Lieberman Dept. of 1 Psychiatry and 2 Computer Science University of North Carolina, Chapel Hill, NC 27614, USA 3 National Institute of Health, Bethesda, MD / March 2003: 1 Summary Enlarged ventricular size and/or asymmetry have been found markers for psychiatric illness, including schizophrenia. We studied ventricular size and shape in volumetric MRI of dizygotic normal twin pairs (DZ), monozygotic normal twin pairs (MZ), and monozygotic twin pairs discordant for schizophrenia (DS), subdivided into affected (DSS) and non-affected (DSH). A fourth group of unrelated matched pairs (NR) was selected from the two normal groups. Left and right ventricles were segmented from high resolution T1 SPGR MRI followed by surface-based shape parametrization. Shape differences between pairs of shape was measured as mean average difference between corresponding surface points. The statistical analysis included two tests with corrections for age and gender: First, we investigated pairwise shape similarity between ventricles of co- twins. The group difference of co-twin similarity between normal MZ and discordant DS was not significant, whereas both groups were significantly different from NR. The pairwise co-twin shape similarity seems equally large for healthy MZ and for MZ-DS, reflecting morphologic similarity due to heritability. Second, we examined the shape difference of the affected and unaffected DS subgroups in comparison to the normal control group. The average shape of normal co-twins not included in group tests served as a template for comparisons. Both the affected and unaffected DS groups showed significant shape difference from the normal population. These tests show ventricular shape alterations from healthy controls not only in the affected (DSS) but also in the non-affected groups (DSH). This leads to the conclusion that ventricular shape change might reflect vulnerability for schizophrenia and hence be a marker for a neurodevelopmental aspect of the illness. Both statistical tests applied to volumes did not show any differences between MZ and DS groups, suggesting that shape analysis is more sensitive to subtle structural changes than volumetry. March 2003: 2 METHODS The T1w high resolution MR image data are processed by automatic brain tissue segmentation followed by shape parameterization. Automatic, atlas- based 3D voxel segmentation technique. Segmentation of lateral ventricles by manually guided 3D connectivity. MZ DZ Twin A Twin B Twin A Twin B Parametrization of object surfaces using 3D Fourier harmonics (SPHARM. [1,3]). Spatial alignment of structures by Procrustes fit of sets of homologous surface points. Size normalization by individual volumes. Pairwise shape difference: Signed and unsigned mean average differences (MAD). Hierarchical surface parameterization by SPHARM Parameterized object surfaces showing correspondences. Subjects and image data Subjects: Image data provided by D. Weinberger, NIMH, Bethesda [2]: MZ: 10 healthy monozygotic twin pairs (N=2*10) DS: 9 MZ twin pairs discordant for schizophrenia (N=2*9) DZ: 10 dizygotic twin pairs, all healthy controls (N=2*10) NR: Selection of unrelated, healthy subject pairs with best possible match of age and gender (N=2*10) Image data: Gradient-echo T1w (256x256x128, 240mm FOV, 1.5mm slice distance) Shape Distance Metric Left Figures: A)Two lateral ventricles showed after alignment. B) Same as A, mesh overlay. C) Surface with color-coded shape distances. Right Figures: Statistical shape analysis providing a significance map (blue: non-significant, red: highly significant)

RESULTS Analysis of ventricle volumes and volume differences: Not significant due to large variability in all groups. Pairwise co-twin shape differences after volume normalization: MZ  DS < DZ < NR, reflecting morphologic similarity due to heritability. Shape differences between groups: We found ventricular shape alterations in affected (DSS) and non-affected (DSH) twins. This might lead to the conclusion that ventricular shape might reflect vulnerability for schizophrenia and might be a marker for neurodevelopmental aspects of illness. CONCLUSIONS Lateral ventricle shapes after volume normalization. Ventricles of 10 DS twin pairs (left) and 5 MZ and 5 DZ pairs (right) are shown side by side. Co-twin Volume Difference Co-twin Shape Similarity References: [1] A. Kelemen, G. Székely, and G. Gerig, „Three-dimensional Model-based Segmentation“, IEEE Transactions on Medical Imaging (IEEE TMI), 18(10): , Oct 1999 [2] A. Bartley, D. Jones, and D. Weinberger, “Genetic variability of human brain size and cortical patterns”,Brain, vol. 120, pp. 257–269, [3] G. Gerig, M. Styner, D. Jones, D. Weinberger, and J. Lieberman, “Shape Analysis of brain ventricles using SPHARM”, in: Proc. Workshop on Math. Methods in Biomed. Image Analysis MMBIA 2001, IEEE Comp Soc, pp , Dec MZ DZ DS Absolute volume differences between co-twins. Volumes were corrected for ICV. Statistics of pairwise differences is corrected for age and gender. There is a trend MZ = MS = DZ < NR, but group tests were not significant except DS versus NR and DZ versus NR. Shape differences between co-twins after normalizing for size differences. There is a significant decrease of shape similarity with decreasing genetic similarity: MZ = DS < DZ < NR. The pairwise shape differences between healthy MZ and MZ-DS are not significantly different. Visualization of the pointwise co-twin distance maps for each group (residuals after correction for gender and age, group averages). The distances are color- coded to show absolute differences between 2 and 8mm. The figures illustrate the decreasing shape similarity MZ = DS < DZ < NR. Healthy MZ are not significantly different from MZ discordant for schizophrenia (DS). Group differences between ventricle shapes Pairwise Co-Twin Differences Volume Analysis Shape distance to healthy control template Volumes corrected for ICV, age and gender. Affected twins (DSS) and nonaffected twins (DSH) do not differ from healthy controls. Shape differences to healthy control template, normalized for unit size and corrected for gender and age. Ventricular shapes of affected twins (DSS) differ significantly from the healthy controls (L: p<0.039, R: 0.058). Ventricular shapes of non-affected twins (DSH) show even more significant differences from healthy controls (L: p<0.0042, R: p<0.0089). Affected versus non-affected twins show no significant group difference. Pointwise averaged distance maps to healthy control template for each group. Distances are color-coded to show localization of shape differences. March 2003: 3 March 2003: 4