1. Age and treatment related local hippocampal changes in schizophrenia explained by a novel shape analysis method 1,2 G Gerig, 3 K Muller, 3 E Kistner, 3 Y Chi, 1 M Chakos, 2 M Styner, 1 JA Lieberman Departments 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 SUMMARY 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. 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 METHODS New 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 clinical variables (age, duration of illness and drug effect)  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 (tail/head) Drug treatment groups (Atypical, Typical) show significant differences of Width Asymmetry measure. Decreasing asymmetry of width with age is found. Deformation and width asymmetry changes in controls analyzed over a ten years interval are not significant. Conclusions w.r.t. age changes from cross-sectional study: Longitudinal study. Exploratory analysis: Requires confirmatory analysis in independent study. CONCLUSIONS Summary of Results Comparison: Longitudinal Shape Change of Controls RESULTS Shape Deformation between Schizophrenics and Controls Patient-Control Euclidean distance differences (shape deformation or bending) at age 20, 30 and 40, left to right. Height indicates the deformation difference between patients and controls in mm. The graph characterizes time slices of the continuous age range. The differences between patients and controls increase over time and are located mostly in the tail and to a lesser extent in the head of the hippocampus. Deformation and width asymmetry changes due to aging within controls for 10 years. Left: Distance model representing shape deformation, scale in mm. Right: Radius model representing left/right asymmetry of local radius change (local width), log-scaled in mm. Shape representation by sampled medial mesh (M-rep). Mesh represents shape with over 99% overlap. Features for Shape Analysis M-rep 3x8 mesh Tail Head M-rep 3x8 mesh Statistical analysis Statistical analysis of 3x8 mesh. Height represents difference. Statistical Model radius Radius: Local width attribute (atrophy, growth). Deformation: Bending, curvature change. L/R Asymmetry of Radius Difference Drug-type versus Control group differences of left to right radius difference log2(L/R), which can be interpreted as L to R local width asymmetry. Left: Typical Drug - Control radius asymmetry difference at age 20, 30 and 40. Right: Atypical Drug – Control radius asymmetry difference. the graphs characterize time slices of the continuous age range and show decreasing asymmetry of local width with age, particularly in the tail and head regions. MICCAI Nov. 2003 Supported by NCI grant P01 CA47982 and the UNC-MHNCRC (MH33127).