Clinical Implication of Multimodal Neuroimaging

1. Clinical Implication of Multimodal Neuroimaging Jungsu S. Oh, Ph.D. Assistant Professor BK21 Division of Human Life Science Seoul National University On behalf of Jun Soo Kwon, M.D., Ph.D. (Clinical Neuroscience and Computational Neuroscience Unit) Professor at BCS, Seoul National University WCU

2. Background • Interests in brain function and connectivity have much grown up in recent decades. • Synergic effects of Multi-modal/Multi-technique Imaging, which is useful • not only for assessing chronic patients • but also for detecting subtle changes in • Ultra-high-risk (UHR) pathological subjects • Neuro-plasticity groups

3. Example of “High-risk” group in the course of schizophrenia Healthy ↑ ↓ Severity of Symptoms

4. Basic Structures of Brain • Gray Matter • Functional activations • Structural imaging • Functional/molecular imaging • White Matter (Tracts) • Connecting distinctive functional regions • Diffusion Tensor MRI for reconstructing pathway information and estimating quantity/quality of anatomical connectivity

5. Basic Principle and Properties of Diffusion Tensor Imaging (DTI) • Mean Diffusivity (Dm) • Size of tensor • (Degree of tissue microstructure disruption) • Fractional Anisotropy (FA) • Sharpness of tensor • Normalized variance of eigenvalues:0~1 • (Degree of fiber integrity) • Mode(Ennis and Kindlmann, MRM, 2006) • Proximity of tensor shape to a disc • Degree of fiber crossing • two principal axes – disc shape • Negative Mode • Crossing fiber tracts: λ1≈ λ2 > λ3 > > Free Water: Isotropic Diffusion White Matter Tracts: Anisotropic Diffusion λ1≈λ2 >λ3

6. Tract (Tractography)-Based DTI Analysis • Not only diffusion properties but “connectivity” • Not only visualization tool but “quantitative analysis tool” of fiber tracts • Tractography Methods • Most Basic: Streamline • Using principal diffusion direction(e1) only • Euler Integration method • Tensorline (regularized, using tensor deflection), level set-based tractography (fast marching tractography) • High-End: Stochastic Tractography and High Angular Resolution Diffusion Imaging (DSI, QBI)

7. Quantitative DTI analysis using Brodmann ROI-based parcellation and tract parameterization Application in Drug-naïve OCD patients Shape-based parameterization (Oh et al., NeuroImage, 2007) (Oh et al., Unpublished data) Application in UHR Schizophrenia patients ? (Oh et al., in preparation) (Oh et al., Human Brain Mapping, in press)

8. N1m MMNm Functional imaging-based estimation of functional activation and connectivity Resting-state fMRI Magnetoencephalogram (MEG) • Decreased desynchronization of alpha rhythm in UHR • Deficits of top-down inhibitory control (Koh et al., Unpublished data) • Deficits of early stage of auditory processing in UHR • N1m and MMNm dipole moments may represent a vulnerability marker in evaluating the risk of transition to psychotic stage in UHR group. (Oh et al., Annual Meeting of Biol Psychiatry 2008) (Shin et al., Biol Psychiatry, in press)

9. Synergic Effects of Multi-modal/Multi-technique Imaging Connectivity Structure Function Brain Imaging BT IT “Biomarker” To Better Understand the Etiology of SZ/ OCD/ … To Better Detect High-Risk Groups for SZ/ OCD/ … Genetics Study BT NT *Abbreviations: SZ: Schizophrenia; OCD: Obsessive-Compulsive Disorder

10. Future Directions of “High Risk” Study Large sample size and longitudinal study Prerequisites • Effective strategies for the recruitment of high-risk groups • Continuous efforts for the “follow-up” studies Combinational approach of structural and functional imaging Functional imaging-based connectivity • Temporal activation in fMRI/MEG • Intersubject variability of FDG PET Structural imaging-based connectivity • Mostly, DTI tractography-based approach Structural Shape • Cortical thickness, CC shape, Basal ganglia shape Genetics-neuroimaging integration

11. An exemplary study of neuro-plasticity groups: the Baduk (Go) game experts Voxel-based DTI analysis Working memory task-related fMRI (Lee et al., Unpublished data) (Park et al., Unpublished data) Integrated Anatomo-Functional Connectivity

12. Conclusion • Multimodal neuroimaging including structural, functional and genetic imaging will add to • finding biomarkers to detect subtle changes in “high risk” groups • facilliating the development of treatment and precaution strategies of psychiatric disorders. • Its application for assessing neuro-plasticity groups (e.g., extraordinary IQ, meditation, Baduk experts) looks promising as well.

13. Seoul Youth Clinic (SYC) Brief history of SYC Procedures in SYC • Started SYC in 16 June, 2004 • Recruited 103 subjects of CHR/GHR SZ - 12 subjects : conversion to psychosis (CHR only) - 18 subjects : drop-up - 73 subjects : follow-up • Mediation: Among the CHR groups, 36 subjects have been taken for antipsychotics. • Related publications - Potential vulnerability markers within the affective domain in subjects at genetic and clinical high risk for schizophrenia. Psychopathology. 2008, Apr - Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia.Schizophr Res. 2008, Feb - Pre-attentive auditory processing in ultra-high-risk for schizophrenia with magnetoencephalography. Biol Psychiatry, in press