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1 NAME: Sheng-Kwei (Victor) Song OMB No and (Rev. 10/15 Approved Through 10/31/2018) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. era COMMONS USER NAME (credential, e.g., agency login): ssong01 POSITION TITLE: Professor EDUCATION/TRAINING INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY Tamkang University B.S Chemistry University of Alabama, Birmingham M.S Physical Chemistry Washington University Ph.D Physical Chemistry Washington University Postdoc Biophysics A. Personal Statement The development of diffusion tensor imaging (DTI) biomarker of white matter injury validated using mouse models of central nervous system (CNS) disorders has been the primary research goal of my lab for the past decade. The approach has been translated to patients of multiple sclerosis (MS) with success. To further improve the sensitivity and specificity of diffusion MRI biomarker of CNS injury, we developed diffusion basis spectrum imaging (DBSI) to correctly estimate axial and radial diffusivity, distinguishing and quantifying coexisting inflammation and/or tissue loss. In addition to the development of the biomarker of CNS injury, we are particularly interested in correlation of nerve functionality with underlying pathologies. We recently demonstrated the first successful diffusion fmri in normal mouse optic nerves proving that diffusion fmri activation is independent of neuronal activation related vascular responses. Subsequently, we applied diffusion fmri to detect white-matter dysfunction in experimental autoimmune encephalomyelitis (EAE) mice at the onset of optic neuritis. 1. Wang Y, Sun P, Wang Q, Trinkaus K, Schmidt RE, et al. Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis. Brain Feb 26;PubMed PMID: Wang Y, Wang Q, Haldar JP, Yeh FC, Xie M, Sun P, Tu TW, Trinkaus K, Klein RS, Cross AH, Song SK. Quantification of increased cellularity during inflammatory demyelination. Brain Dec;134(Pt 12): PubMed PMID: ; PubMed Central PMCID: PMC Spees WM, Lin TH, Song SK. White-matter diffusion fmri of mouse optic nerve. Neuroimage Jan 15;65: PubMed PMID: ; PubMed Central PMCID: PMC Chiang CW, Wang Y, Sun P, Lin TH, Trinkaus K, Cross AH, Song SK. Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. Neuroimage Nov 1;101: PubMed PMID: ; PubMed Central PMCID: PMC B. Positions and Honors Positions and Employment Research Associate, Operations Director of Biomedical MR Lab, WU, St. Louis, MO Senior Scientist, Operations Director of Biomedical MR Lab, WU, St. Louis, MO Instructor in Radiology, Washington University School of Medicine, St. Louis, MO Assistant Professor of Radiology, Washington University School of Medicine, St. Louis, MO Associate Professor of Radiology, Washington University School of Medicine, St. Louis, MO 2012 Professor of Radiology, Washington University School of Medicine, St. Louis, MO

2 Other Experience and Professional Memberships 1990 International Society of Magnetic Resonance 2007 The Association for Research in Vision and Ophthalmology 2008 Society for Neuroscience 2015 Biomedical Engineering Society Neurobiology C Merit Review Subcommittee, VA Medical Research Services, Ad Hoc Reviewer Neurobiology C Merit Review Subcommittee, VA Medical Research Services, member NIH Clinical Neuroimmunology and Brain Tumors (CNBT) Study Section, Ad Hoc Reviewer 2010 CDMRP_MSRP_FY09_ Panel National Multiple Sclerosis Society Clinical and Translational Study Committee, member NIH Clinical Neuroimmunology and Brain Tumors (CNBT) Study Section, member Honors 2016 Fellow, American Institute for Medical and Biological Engineering 2016 Distinguished Investigator of the Academy of Radiology Research 2017 Distinguished Investigator Award, Washington University School of Medicine Patent Y. Wang, Q. Wang, S.K. Song, Diagnosis of Central Nervous System White Matter Pathology Using Diffusion MRI USA Patent. Serial No. 61/345,367. Ze-Zhong Ye and Sheng-Kwei Song, Quantitative Differentiation of Inflammation from Solid Tumors, Heart and Nerve Injury Provisional patent filed on 8/30/2016. C. Contribution to Science Diffusion tensor imaging (DTI) derived eigenvalues have often been combined into summary or secondary parameters that allow a simplified expression of water diffusion characteristics. The two most common summary parameters are apparent diffusion coefficient (ADC, the mean of the three eigenvalues), and the fractional anisotropy (FA, the normalized standard deviation of the three diffusivities). ADC and FA, though convenient and sensitive to tissue pathology and morphology, lack specificity and propagate uncertainty (noise) from each of the three eigenvalues. To address the shortcomings of ADC and FA, I proposed a simple concept employing eigenvalues to directly assess CNS white matter integrity. Specifically, I proposed that decreased axial diffusivity (AD, the largest eigenvalue describing diffusion along axonal fiber tracts) reflects axonal injury while increased radial diffusivity (RD, the averaged of the rest two eigenvalues describing diffusion perpendicular to axonal fiber tracts) indicates myelin injury. My lab has led the filed in quantitative histological validation of in vivo DTI derived AD/RD as axon and myelin injury biomarkers. The following initial three manuscripts detailing the concept and histology validation have been cited over 3,000 times in combination. a. Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH. Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage Nov; 17 (3): PubMed PMID: b. Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH. Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage Nov;20(3): PubMed PMID: c. Song SK, Yoshino J, Le TQ, Lin SJ, Sun SW, Cross AH, Armstrong RC. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage May 15;26(1): PubMed PMID: DTI demonstrates an improved capability over standard magnetic resonance imaging to differentiate axon from myelin pathologies. However, the increased cellularity and vasogenic edema associated with inflammation cannot be detected or separated from axon/myelin injury by diffusion tensor imaging, limiting its clinical applications. Worst of all, these pathological components interfere with DTI measured AD/RD significantly decreasing DTI sensitivity and specificity to axon and myelin injury. Thus, we developed a novel, data-driven

3 diffusion basis spectrum imaging (DBSI) to quantitatively reveal white matter pathologies to accurately characterize water diffusion properties associated with axon/myelin injury and inflammation in CNS disorders. DBSI is capable of noninvasively quantifying axonal injury, demyelination, and inflammation in a single measurement. DBSI can be used to directly assess the extent of inflammation (cell infiltration and edema), axonal injury/loss, and demyelination. a. Wang Y, Sun P, Wang Q, Trinkaus K, Schmidt RE, et al. Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis. Brain Feb 26;PubMed PMID: b. Chiang CW, Wang Y, Sun P, Lin TH, Trinkaus K, Cross AH, Song SK. Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. Neuroimage Nov 1;101: PubMed PMID: ; PubMed Central PMCID: PMC c. Wang X, Cusick MF, Wang Y, Sun P, Libbey JE, Trinkaus K, Fujinami RS, Song SK. Diffusion basis spectrum imaging detects and distinguishes coexisting subclinical inflammation, demyelination and axonal injury in experimental autoimmune encephalomyelitis mice. NMR Biomed May 12;PubMed PMID: d. Wang Y, Wang Q, Haldar JP, Yeh FC, Xie M, Sun P, Tu TW, Trinkaus K, Klein RS, Cross AH, Song SK. Quantification of increased cellularity during inflammatory demyelination. Brain Dec;134(Pt 12): PubMed PMID: ; PubMed Central PMCID: PMC Currently functional MRI (fmri) studies are limited almost exclusively to gray matter, and rely upon coupling of hemodynamic response to functional activation. Signal modulations on the order of 1 5% are typical. The limited capacity for physiologic modulation of blood flow and the inherently lower fractional blood volume probably account for the difficulty in monitoring white-matter functional activation with standard BOLD (blood oxygen level dependent) fmri techniques. Thus, at present, white-matter MRI is largely restricted to probing the structural integrity of fiber tracts using DTI or variants thereof. Using diffusion MRI, we reported for the first time that a visual-stimulus-induced 27% decrease in ADC of water perpendicular to the axonal fibers (ADC ) is demonstrated for C57BL/6 mouse optic nerve in vivo. No change in ADC (diffusion parallel to the optic nerve fibers) was observed during visual stimulation. A possible vascular contribution was ruled out by carrying out the ADC measurements in hypercapnic mice with and without visual stimulus, observing no effect from hypercapnia. Subsequent application of diffusion fmri detected optic nerve dysfunction in experimental autoimmune encephalomyelitis (EAE) mice at the onset of optic neuritis. a. Spees WM, Lin TH, Song SK. White-matter diffusion fmri of mouse optic nerve. Neuroimage Jan 15;65: PubMed PMID: ; PubMed Central PMCID: PMC b. Lin TH, Spees WM, Chiang CW, Trinkaus K, Cross AH, Song SK. Diffusion fmri detects white-matter dysfunction in mice with acute optic neuritis. Neurobiol Dis Jul;67:1-8. PubMed PMID: ; PubMed Central PMCID: PMC Complete List of Published Work D. Research Support Ongoing Research Support P01- NS Cross (PI) 05/01/14 04/30/19 NIH/NINDS Biomarkers and Pathogenesis of MS: From Mouse to Human This is a program project to study diffusion basis spectrum imaging and its ability to reflect pathology and blood-brain barrier properties in mouse models and patients with multiple sclerosis. In Project 1 Validating diffusion MRI biomarkers of inflammation and axon pathologies in EAE (PI Song), the feasibility of using DBSI as a surrogate of neuropathology in the living EAE mouse optic nerve and spinal cord will be validated with IHC. The detected white matter pathologies will also be correlated with axonal transport measured using MEMRI. Core C Image Data Acquisition, Analysis, and Modeling Core will facilitate projects 2 and 3 and develop myelin water-dbsi cross-check and correlation.

4 Role: PI of Project 1 and Core C RG 5258-A-5 Song (PI) 10/1/ /30/2017 NMSS Understanding the pathophysiology underlying MS progression In this study, we proposed to conduct longitudinal assessments of optic nerve pathologies (by in vivo DBSI) and function (using diffusion fmri) of ON-affected optic nerves in EAE mice with and without treatments to decipher the potential mechanism leading to the eventual visual impairment in ON. U01-EY Song (PI) 05/01/ /30/2020 NIH/NEI Imaging optic nerve function and pathology In this proposed study in response to NEI Audacious Goal Initiative RFA, we will developed diffusion basis spectrum imaging (DBSI) to simultaneously imaging optic nerve function and pathologies in multiple sclerosis and glaucoma, from mouse to human. R21NS (MPI, Naismith/Song) 09/30/ /31/2017 (no cost extension) NIH Noninvasively Distinguishing Inflammation from Tissue Injury in Optic Neuritis This proposal will translate DBSI to quantify individual components of the evolving histopathology in optic neuritis using OCT, VEP, and contrast sensitivity as endpoint measures. We seek to apply the DBSI method to optic nerve imaging with an improved reduced field-of-view diffusion MRI sequence and postprocessing/analysis pipeline, and to create a complete acquisition/analyses package available to multiple centers for collaborative trials. R01 NS (MPI, Song/Ray) 07/01/ /30/2022 NIH Cervical spondylotic myelopathy is the most common form of spinal cord injury and is a significant public health problem. The identification of non-invasive methods to assess preserved spinal cord integrity and predict functional recovery would represent a new and exciting advance in the treatment of these patients. This project seeks to identify and validate imaging markers that reliably assess preserved tissue and are predictive of functional recovery in patients with cervical spondylotic myelopathy. Completed Research Support Idea Award Song (PI) 10/1/2012 9/30/2016 Department of Defense Noninvasive detection and differentiation of axonal injury/loss, demyelination, and inflammation in MS In this study, we proposed examine the evolution of corpus callosum de-/re-myelination, and inflammation using in vivo DBSI and IHC. In addition, EAE mice will be examined correlating visual acuity with optic nerve DBSI determined pathology, validated with IHC. R01 NS Song (PI) 04/01/05 06/30/15 NIH/NINDS Evaluation of Spinal Cord White Matter Injury using DTI In this study, we propose to use the currently available DTI technology to establish a direct link between directional diffusivities and underlying white matter pathologies during SCI. Specifically, we will use mouse models of SCI with highly-specific, well defined pathology to quantify DTI parameters relating primarily: myelin degeneration (Aim 1), axonal injury followed by demyelination (Aim 2), and inflammation with/without axonal and myelin injury (Aim 3). RG459A4/1 Song (PI) 09/30/11 09/30/14 NMSS

5 Noninvasive Quantification of Axon I in EAE and MS In this study, we proposed to examine the spinal cord of EAE mice with and without steroid treatment for the developing the diffusion MRI biomarker derived using the newly developed diffusion basis spectrum imaging (DBSI). Both progressive and relapsing-remitting EAE will be studied followed by a pre-clinical test of DBSI on autopsy MS CNS tissues.