1. Guido Gerig, UNC, Feb. 2003 Part III Statistical Characterization of Brain Structures via M-reps Guido Gerig Departments of Computer Science and Psychiatry UNC Chapel Hill

2. Guido Gerig, UNC, Feb. 2003 Morphometry of Anatomical Structures UNC Chapel Hill: Morphometry of brain structures in: –Schizophrenia –Twin Studies (MZ/DZ/DS) –Autism, Fragile-X –Alzheimer’s Desease –Depression –Epilepsy –… Ventricles: lateral ventricle 3 rd ventricle temporal horn caudate nucleus hippocampus

3. Guido Gerig, UNC, Feb. 2003 Representative Clinical Study: Neuropathology of Schizophrenia When does it develop ? Fixed or Progressive ? Neurodevelopmental or Neurodegenerative ? Neurobiological Correlations ? Clinical Correlations ? Treatment Effects ? Noninvasive neuroimaging studies using MRI/fMRI to study morphology and function

4. Natural History of Schizophrenia Age (Years) Good Function/ Psycho- pathology Poor 15203040506070 Premorbid ProdromalProgressive Chronic/Residual Gestation/ Birth

5. Guido Gerig, UNC, Feb. 2003 Study: Structural analysis of caudate nucleus in Schizophrenia Processing Steps Automatic whole brain tissue classification (EM segm.) User-operated masking of caudate on label image (intra-, interrater reliability > 0.95) Surface parametrization of caudate shapes  SPHARM & PDM Alignment/Normalization: Surface Correspondence Medial mesh generation (m-rep model)

6. Guido Gerig, UNC, Feb. 2003 Modeling of Caudate Shape M-rep PDM Surface Parametrization PDM M-rep

7. Guido Gerig, UNC, Feb. 2003 Basal Ganglia Netter’s Atlas of Human Anatomy Ventricles: lateral ventricle 3 rd ventricle temporal horn caudate nucleus hippocampus

8. Guido Gerig, UNC, Feb. 2003 Caudate Shape Analysis Clinical Groups: –Healthy controls (N=30) –Typical drug treatment (30) –Atypical drug treatment (30) Clinical questions: –Shape difference between groups? –Drug/patient interaction? –Location & type of changes CNTL Atyp Typ Mean Shapes per Group

9. Guido Gerig, UNC, Feb. 2003 Caudate volume analysis *preliminary analysis, not controlled for age Significantly larger volumes of SZ versus controls Trend but not significant difference between Typ/Atyp Where and what is difference?

10. Guido Gerig, UNC, Feb. 2003 Mean Shapes CNTL vs. SZ leftright Overlay of aligned (transl/rot) original shapes: green: CNTL / purple mesh: SZ

11. Guido Gerig, UNC, Feb. 2003 Mean Shapes CNTL vs. SZ leftright Overlay of size normalized* shapes: green: CNTL / purple mesh: SZ *shape should not reflect size change

12. Guido Gerig, UNC, Feb. 2003 Alignment, Correspondence? –Choice of alignment coordinate system? –Establishing correspondence is a key issue for building statistical shape models. –Various methods for definition of correspondence exist (landmarks, high dimensional warping, PDM w. MDL refinement, …). –Resulting eigenmodes of deformation depend on these definitions. –Scaling of objects prior to shape analysis?

13. Guido Gerig, UNC, Feb. 2003 Object Alignment / Surface Homology MZ pair DZ pair Surface Correspondence

14. Guido Gerig, UNC, Feb. 2003 Object Alignment before Shape Analysis 1 st elli TR, no scal1 st elli TR, vol scalProcrustes TRS top side

15. Guido Gerig, UNC, Feb. 2003 Correspondence through parameter space rotation Normalization using first order ellipsoid: Rotation of parameter space to align major axis Spatial alignment to major axes Parameters rotated to first order ellipsoids

16. Guido Gerig, UNC, Feb. 2003 Correspondence ctd. Rhodri Davies and Chris Taylor –MDL criterion applied to shape population –Refinement of correspondence to yield minimal description –83 left and right hippocampal surfaces –Initial correspondence via SPHARM normalization –IEEE TMI August 2002

17. Guido Gerig, UNC, Feb. 2003 Correspondence ctd. Homologous points before (blue) and after MDL refinement (red). MSE of reconstructed vs. original shapes using n Eigenmodes (leave one out). SPHARM vs. MDL correspondence.

18. Guido Gerig, UNC, Feb. 2003 Shape Representation Method: Medial Representation M-rep Implied Surface Skeletal Mesh (sampled) Local Width (Radius) Implied shape represents original shape with 99% volume overlap and  =0.05 MAD at boundary (M. Styner, PhD thesis)

19. Guido Gerig, UNC, Feb. 2003 Shape Difference Analysis of M-rep Mesh PositionLocal Width A and B aligned, superimposed Mesh distance at corresponding nodes: Object deformation, Bending Radius difference at corresponding nodes: Local width change Grp B Grp A

20. Guido Gerig, UNC, Feb. 2003 Statistical Analysis Shapes represented by m-rep: Significant feature reduction, multi- scale Still: Number of features  sample size. Variability hides shape changes. Shapes not represented by scalar values: Standard MANOVA analysis inappropriate. Often: PCA on features, selection of small # of Eigenmodes, Fisher linear discriminant, leave one out test for classification. But: Fisher LD not robust, #of features?, feature selection?, does PCA reflect group differences?

21. Guido Gerig, UNC, Feb. 2003 radius mesh distance Statistical Analysis

22. Guido Gerig, UNC, Feb. 2003 Shape analysis using medial representations Local width (radius) differences: Growth, Atrophy (Loss) Positional differences: Bending, Deformation radius

23. Guido Gerig, UNC, Feb. 2003

24. Permutation Test Monte Carlo Sampling (m=k=30) Mean differences from 1000 permutations Test original difference 22.8 versus distribution: p=0.025 #experiments

25. Guido Gerig, UNC, Feb. 2003 Results Caudate Shape Analysis Integrated local effects Typical group shows larger shape difference to controls than atypical group Significant shape difference between typical and atypical treatment group Shape distances not shown in combined SZ versus controls analysis Treatment effect or clinical selection bias? Experimental study design, result need to be verified in cross-validation study *Non-parametric permutation test

26. Guido Gerig, UNC, Feb. 2003 Results Caudate Shape Analysis Comparison of Surfaces Right: CNTL – AtypRight: Atyp – TypRight: CNTL – Typ Right: CNTL – Atyp -Typ CNTL Atyp Typ Significant shape changes mostly in the head of the caudate Shape effect on left side larger than on right side Local significance tests in progress

27. Guido Gerig, UNC, Feb. 2003 Shape Difference: Where and What? Local Mesh Deformation Atypical versus Typical drug treatment groups (N = 30) Local Deformation (Euclidean dist. between corresponding nodes) Local significance tests (nonparametric permutation tests) p-values per mesh nodemesh with nodes p<0.05 mesh with node differences p<0.01

28. Guido Gerig, UNC, Feb. 2003 mesh with nodes p<0.05 Group B Group A Shape Difference: Where and What? Local Mesh Deformation Atypical versus Typical drug treatment groups (N = 30) Local Deformation (Euclidean dist. between corresponding nodes)

29. Guido Gerig, UNC, Feb. 2003 Atypical versus Typical drug treatment groups (N_atyp=N_typ = 30) Local Width Diff. (Radius diff. between corresponding node positions) Local significance tests (nonparametric permutation tests) p-values per mesh nodemesh with nodes p<0.05 mesh with node differences p<0.05 Shape Difference: Where and What? Local Width Difference

30. Guido Gerig, UNC, Feb. 2003 Atypical versus Typical drug treatment groups (N_atyp=N_typ = 30) Local Width Diff. (Radius diff. between corresponding node positions) mesh with nodes p<0.05 Group A Group B Shape Difference: Where and What? Local Width Difference

31. Guido Gerig, UNC, Feb. 2003 Atypical versus Typical drug treatment groups (N_atyp=N_typ = 30) Local Width Diff. (Radius diff. between corresponding node positions) Shape Difference: Where and What? Local Width Difference Morphing between Atypical (thinner) and Typical (thicker)

32. Guido Gerig, UNC, Feb. 2003 Discussion Caudate Study Netter’s Atlas of Human Anatomy Width and mesh deformation mostly in caudate body/head. Secondary mesh deformation posteriorly Typical treatment group differs from Controls, but not Atypical. Clinical implications? Study caudate shape change relative to neighboring shapes.

33. Guido Gerig, UNC, Feb. 2003 IRIS: Tool for interactive image segmentation. Manual contouring in all orthogonal sections. 2D graphical overlay and 3D reconstruction. Hippocampus segmentation protocol (following Duvernoy). Hippocampus: reliability >0.95 intra-, >0.85 inter- rater) Study: Hippocampal Shape in Schizophrenia

34. Guido Gerig, UNC, Feb. 2003 Hippocampal Volume Analysis Left smaller than right SZ smaller than CNTRL, both left and right Variability SZ larger than CNTL

35. Guido Gerig, UNC, Feb. 2003 3D Shape Variability: Left Hippocampus of 90 Subjects

36. Guido Gerig, UNC, Feb. 2003 Hippocampal Shape Analysis Left and right hippocampus: Comparison of mean shapes CNTL-SZ (signed distance magnitude relative to SZ template) leftright outin LeftRight Movie: Flat tail: SZ, curved tail: CNTL

37. Guido Gerig, UNC, Feb. 2003 Hippocampus M-rep: Global & Local Statistical Analysis Hippocampus: Integrated difference to template shape (structures size normalized) Width (p<0.75)Deformation (p<0.0001) p<0.01 individual m- rep local group discrimination statistics SZ CNTL G. Gerig & M. Styner

38. Guido Gerig, UNC, Feb. 2003 Local Statistical Tests Medial representation study confirms: Hippocampal tail is region with significant deformation.

39. Guido Gerig, UNC, Feb. 2003 Statistical Analysis of M-rep representations *Work in progress Keith Muller, Emily Kistner, M. Styner, J. Lieberman, G. Gerig, UNC Chapel Hill Systematic embedding of interaction of age, duration of illness and drug type into local statistical analysis Correction for multiple tests Difference in hippocampus shape between SZ and CNTRL as measured by M-rep deformation *Repeated measures ANOVA, cast as a General Linear Multivariate Model, as in Muller, LaVange, Ramey, and Ramey (1992, JASA). Exploratory analysis included considering both the "UNIREP" Geisser-Greenhouse test and the "MULTIREP" Wilks test. M-rep 3x8 mesh Tail Head

40. Guido Gerig, UNC, Feb. 2003 Patient-CNTL Deformation Difference at Age 40 Patient-CNTL Deformation Difference at Age 30 Patient-CNTL Deformation Difference at Age 20 Deformation at mesh nodes (mm) AGE Model: Row x Col x Drug (y/n) x Age: p = 0.0097 Tail Head Difference in hippocampus shape between patients and controls: Located mostly in the tail of the hippocampus, becomes more pronounced over time.

41. Guido Gerig, UNC, Feb. 2003 Comparison to CNTLs Change in hippocampus shape over ten years for controls Tail Head Deformation at mesh nodes (mm)

42. Guido Gerig, UNC, Feb. 2003 Patients vs. Controls: Local width L/R asymmetry analysis Typical DrugAtypical Drug Radius diff. at mesh nodes log (mm) Model: Row x Col x Drug type x Age & Left/Right width asymmetry: p = 0.0097 AGE 20 30 40 20 30 40

43. Guido Gerig, UNC, Feb. 2003 Preliminary conclusions local asymmetry of width analysis Reduction in control/patient difference in hippocampus width asymmetry seems more pronounced in the atypical group. Differences between patients and controls in hippocampus width asymmetry decrease over time. 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. Atypical treated patients start (at an early age) less far from the normals than do those treated with typical drugs (TREATMENT EFFECT OR CLINICAL SELECTION BIAS?).

44. Guido Gerig, UNC, Feb. 2003 Conclusions Shape represents changes not reflected by volume analysis Several clinical studies: Shape discriminates better than volume M-rep superior to boundary models –separate analysis of local width/bending –results explained in natural language terms –potential to analyze figure-subfigure relationships and figures in anatomic context Improved statistical framework for discrimination in development

45. Guido Gerig, UNC, Feb. 2003 Acknowledgements Martin Styner Sean Ho Sampath Vetsa Keith Muller Jeffrey A. Lieberman Stephen M. Pizer and M-rep team Talk at: http://midag.cs.unc.edu