2. Diffusion Physics - Thermal Agitation - In steady state, the motion of water is dominated by thermal agitation. -This causes “random” motion of water within a compartment.

3. Diffusion Physics - Thermal Agitation -The “rate” of water motion is determine by a diffusion coefficient, “D”. -Mean displacement of water molecules is related to “D” by Einstein’s equation:

4. Detecting Diffusion with MRI - Intravoxel Incoherent Motion From Ellingson, Concepts in MR, 2008

5. Detecting Diffusion with MRI - Intravoxel Incoherent Motion Detected DWI Signal MRI Signal w/o Diffusion Sensitivity Phase of “Tagged” H 2 OFunction of Diffusion Gradients Diffusion Coefficient

6. Factors that affect diffusion coefficient, D -Diffusion Time, t -Physical time between gradients used to “tag” H 2 O -Size of Compartment(s) - If we set a limit for  r, then we observe an apparent diffusion coefficient, ADC -Tortuosity of the Compartments - More tortuous paths look like slow diffusion -Temperature -Viscosity *** We can only measure “ADC” because of all the factors that change “D”! ***

7. Diffusion Tensor Imaging (DTI) Diffusion anisotropy can occur when compartments are not symmetric Diffusion may be higher in different directions To determine diffusion anisotropy, we use Diffusion Tensor Imaging (DTI) DTI uses diffusion sensitizing gradients to determine ADC in different directions From these measurements we construct the mathematical tensor In this way, DTI more accurately models the geometry of tissues Isotropic Diffusion Anisotropic Diffusion

8. Diffusion Tensor Imaging (DTI) The Diffusion Tensor: Isotropic Diffusion 1 = 2 = 3 Anisotropic Diffusion 1 > 2, 3 From Ellingson, Concepts in MR, 2008

9. Davidoff, A., Handbook of the Spinal Cord MR constraints largely limit ADC measurement to the extracellular compartment. Diffusion in the spinal cord is highly anisotropic for both gray matter and white matter Diffusion MR Characteristics of the Central Nervous System From A.Todd, Univ. GlascowFrom Ellingson, Concepts in MR, 2008

10. Transverse ADC (tADC) is dependent on (Schwartz, 2005) –  Axon Counts =  tADC –  Extracellular Volume =  tADC –  Myelin Volume =  tADC Longitudinal ADC (lADC) is dependent on (Song, 2003; 2002; Sun, 2006; Ellingson, 2008) –Structural and Functional Integrity of Axons –Microfilament & Neurofilament Density –Axonal Transport System Integrity Diffusion MR Characteristics of the Central Nervous System From Ellingson, Concepts in MR, 2008

11. DTI Tractography In the CNS, lADC > tADC & 1 is parallel to axon orientation

12. ADC is consistent across pulse sequences (Ellingson, AJNR, 2008) Ellingson, 2008 Diffusion MR Characteristics of the Central Nervous System Anisotropy is preserved across surrogates (Ellingson, Concepts in MR, 2008)

13. Diffusion MR Characteristics of the Central Nervous System ADC changes across the length of the spinal cord (Ellingson, AJNR, 2008; Ellingson, JMRI, 2008) Human Rat RostralCaudal

14. Pathology & DTI in Spinal Trauma

15. Pathology of Acute SCI Mechanical Injury: –Stretching and tearing of axons  immediate death of all damaged cells. Hypoxia and Ischemia: –Blood flow to injury is restricted. –Anaerobic metabolic processes in viable tissue, other tissues become necrotic. Hemorrhage & Vasogenic Edema: –In contusion injury, hemorrhages start in central gray matter and spread radially. –Early vasogenic edema forms due to blood constituents leaving vasculature. Damage to Axon Transport Systems: –Microtubules and neurofilaments begin to degrade. NormalMechanical Injury Vasogenic Edema From Ellingson, Concepts in MR, 2008

16. DTI in Acute SCI Mechanical Injury: –Overall ADC  at lesion site due to lack of boundaries to diffusion Hypoxia and Ischemia: –Cause ADC  Hemorrhage & Edema: –Causes ADC  at lesion site due to lack of boundaries to diffusion Damage to Axon Transport Systems: –Causes lADC  Rat - Ex Vivo (Ellingson, JMRI, 2008b) lADCtADC From Ellingson, Concepts in MR, 2008

17. Pathology of Subacute SCI Reactive Cells: –Active microglia increase in density –Active Astrocytes hypertropy and line the cavity wall Anterograde and Retrograde Degeneration: –Axons form retraction bulbs at proximal ends –Demyelination occurs –Proximal axons begin to swell –Distal axons are dissolved Gray Matter Morphological Changes: –Damaged axon nuclei move to eccentric locations within the cell body. –Neurons begin to hypotrophy and dendrites retract Cytotoxic Edema –Axons and soma swell, the extracellular space decreases Normal Reactive Cells Cytotoxic Edema From Ellingson, Concepts in MR, 2008

18. DTI in Subacute SCI Reactive Cells: –Glial scar changes 1 orientation (Schwartz, 2005) –High density microglia  ADC –Tortuosity from activated astrocytes causes  ADC Anterograde and Retrograde Degeneration: –tADC  during demyelination –lADC  due to axon transport damage –ADC  due to axon swelling Gray Matter Morphological Changes: Vasogenic Edema –Axons and soma swell, the extracellular space decreases –This causes  ADC Rat - Ex Vivo (Ellingson, JMRI, 2008b) lADC tADC From Ellingson, Concepts in MR, 2008

19. Pathology of Chronic SCI Long-term Axon Degeneration –Progressive demyelination –Loss of large diameter axons –Widespread spreading of cysts –Retrograde & Transneuronal degeneration damages whole spinal tracts Gray Matter Morphology Changes –Chromatolysis –Nuclear Changes Spinal Cord Atrophy NormalAtrophy + Axon Loss Normal MNs Chronic SCI MNs From Ellingson, Concepts in MR, 2008

20. DTI in Chronic SCI Cavity Formation Remote Changes Rat - Ex Vivo (Ellingson, JMRI, 2008b)

21. DTI in Chronic SCI Rat - Ex Vivo (Ellingson, JMRI, 2008b)

22. DTI in Chronic SCI Chronic Human SCI (Ellingson, AJNR, 2008b) C5 Complete Injury Rostral-Caudal Asymmetry at Lesion Epicenter

23. Functional Correlates of DTI Axonal Damage (Song, 2003; 2002; Nair, 2005; Sun, 2006) ↓ Longitudinal ADC (lADC) Myelin Damage (Song, 2003; 2002; Nair, 2005; Sun, 2006) ↑ Transverse ADC (tADC)

24. Functional Correlates of DTI Normal SCI No temporal Coherence Loss of Amplitude

25. Functional Correlates of DTI C-fiber input to LSTT (Valeriani, 2007; Li, 1991; Latash, 1988) A  -fiber input to MSTT (Valeriani, 2007; Latash, 1988) Ellingson, J Neurotrauma, 2008, In Press

26. Functional Correlates of DTI From Ellingson, Biomed Sci Instrum, 2008 & Congress Neurological Surgeons, 2008

27. Conclusions DTI is highly sensitive to the structural integrity of the spinal cord. DTI can be used to monitor the progression of SCI from acute through chronic stages DTI may also be sensitive to the functional integrity of the spinal cord. Future studies will be aimed at determining if DTI can predict long-term functional recovery in incomplete SCI

28. Thank You Brian Schmit, Ph.D., Dept. of Biomedical Eng., Marquette University Shekar Kurpad, M.D., Ph.D., Dept. of Neurosurgery, MCW John Ulmer, M.D., Dept. of Radiology, MCW Maria Crowe, Ph.D., Dept. of Neurosurgery, MCW Kathleen Schmainda, Ph.D., Dept. Radiology & Biophysics, MCW Kristina Ropella, Ph.D., Dept. Biomed. Eng., Marquette University Funding: –NIH R21, Brian Schmit (PI) –Falk Foundation –Marquette University –VA Medical Center, Milwaukee, WI –Bryon Riesch Paralysis Foundation