1. Age and treatment related local hippocampal changes in schizophrenia explained by a novel shape analysis method 1,2 G Gerig, 2 M Styner, 3 E Kistner, 3 Yueh-Yun Chi, 3 K Muller, 1 JA Lieberman Depts. of 1 Psychiatry, 2 Computer Science, 3 Biostatistics University of North Carolina, Chapel Hill, NC 27614, USA gerig@cs.unc.edu / http://www.cs.unc.edu/~gerig March 2003: 1 Volume reduction of the hippocampus observed with MRI is one of the most consistently described structural abnormalities in patients with schizophrenia. However, the timing, the association with treatment, and an intuitive explanation of morphologic changes are not known. This study analyzed subtle changes of the hippocampal structure in schizophrenics (N=57) as compared to matched controls (N=26). The effect of age, duration of illness and drug type to local shape changes was studied with a new shape representation technique and an exploratory statistical analysis. The M-rep shape representation model allows a separate analysis of shape deformation and of local atrophy. The exploratory statistical model was a repeated measures ANOVA, cast as a general linear multivariate model. The exploratory nature of the analysis means that the promising results must be replicated in order to provide full confidence in the conclusions. March 2003: 2 Quantitative 1.5 Tesla MRI examinations of the brain were utilized to examine a young patient group in the early illness stage of illness (N=34) and an older group of schizophrenic patients who were chronically ill (N=22). MRI examinations of the brain were also acquired for 26 right-handed male controls matched to both patient groups for age and handedness (young controls N=14, older controls N=12). Patients were characterized with regards to duration of illness and illness severity utilizing PANSS assessments. At the time of scan, 17 early illness patients were on typical antipsychotic medication (haloperidol), and 17 were on atypical antipsychotic medications (13 olanzapine, 4 on risperidone). For chronic patients, only 5 were on typical medications (3 haloperidol, 1 tri u-perazine and 1 thiothixene), and 18 were on atypical medications (6 olanzapine, 8 clozapine and 4 risperidone). Subjects and Image Data IRIS: Tool for interactive image segmentation. Manual painting in orthogonal sections. 2D graphical overlay and 3D reconstruction. 2D/3D cursor interaction between cut-planes and 3D display. Hippocampus: Intra-rater Reliability: 0.95/0.92 Software available online: http://midag.cs.unc.edu Segmentation of hippocampal structures Object shape parameterization SUMMARY METHODS Implied Surface Skeletal Mesh (sampled) Local Width (Radius) radius Features for Shape Analysis Radius: Local width attribute (atrophy, growth). Deformation: Bending, curvature change. Shape representation by sampled medial mesh (M-rep). Mesh represents shape with over 99% overlap. M-rep 3x8 mesh Tail Head M-rep 3x8 mesh Statistical analysis Statistical analysis of 3x8 mesh representati on. Height represents difference. Statistical Model

2. March 2003: 4 References: [1] A. Kelemen, G. Székely, and G. Gerig, „Three-dimensional Model-based Segmentation“, IEEE Transactions on Medical Imaging (IEEE TMI), 18(10):828-839, Oct 1999 [2] G. Gerig, M. Styner, D. Jones, D. Weinberger, and J. Lieberman, “Shape Analysis of brain ventricles using SPHARM”, in: Proc. Workshop on Mathematical Methods in Biomedical Image Analysis MMBIA 2001, IEEE Comp. Soc., pp. 171- 178, Dec. 2001 [3] G Gerig, M Styner, ME Shenton, JA Lieberman, Shape versus Size: Improved Understanding of the Morphology of Brain Structures, Proc. MICCAI 2001, Springer LNCS 2208, pp. 24-32, Oct. 2001 CONCLUSIONS New shape representation and statistical analysis scheme overcomes problem of feature reduction/selection from high-dimensional shape representation. Analysis does not require correction for multiple tests as in schemes using a high number of surface-based statistical tests. Systematic integration of shape with age, duration of illness and drug effect parameters  Leads to intuitive answers in regard to treatment effects and longitudinal changes. Significant hippocampal deformation difference between schizophrenics and controls (p<0.0091). Deformation increases with age. Differences are located mostly in the tail and to a lesser extent in the head of the hippocampus. Drug treatment groups (Atypical, Typical) show significant differences of Radius Asymmetry measure (Left-Right Radius difference). Decreasing asymmetry of width with age is found. Deformation and width asymmetry changes in controls analyzed over a ten years interval are not significant. Exploratory analysis RESULTS Comparison: Longitudinal Shape Change of Controls Shape Deformation between Schizophrenics and Controls L/R Asymmetry of Radius Difference Summary of Results This exploratory analysis on the 79 subject dataset demonstrates a new technique for statistical analysis of shapes in combination with clinical variables. Following this study, we will continue with an confirmatory analysis in an independent schizophrenia study where all hypothesis would be specified and fixed a priory before data would be collected. This study would allow either replication or rejection of results shown here. Given the expected atrophy over time due to aging, it seems that the hippocampus of a young schizophrenic looks like the hippocampus of an older control, and the two groups look more alike later in time. Furthermore, the atypical treated patients start (at an early age) less far from the normals than do those treated with typical drugs. March 2003: 3