1. Functional Correlates of Diffusion Tensor Imaging in Spinal Cord Injury Benjamin M. Ellingson, Ph.D. 1,2 Shekar N. Kurpad, M.D., Ph.D. 2 Brian D. Schmit, Ph.D. 1 1 Department of Biomedical Engineering, Marquette University 2 Department of Neurosurgery, Medical College of Wisconsin

2. Motivation Traditional MRI is not sensitive to axonal injury (Falconer, 1994; Kulkarni, 1988)  Traditional MRI is no better than neurological exam (Flanders, 1999; Shepard, 1999; Bondurant, 1990) Diffusion Tensor Imaging (DTI) is more sensitive to axon injury (Ford, 1994; Schwartz, 2003) Objective: Determine if DTI is sensitive to quantitative measures of sensory function (i.e. electrophysiology).

3. Diffusion Tensor Imaging (DTI) DTI uses MRI gradients to “tag” diffusing H 2 O molecules Apparent Diffusion Coefficient (ADC) is dependent on boundaries to diffusion lADC tADC

4. Differential Sensitivity of DTI Axonal Damage (Song, 2003; 2002; Nair, 2005; Sun, 2006) ↓ lADC Myelin Damage (Song, 2003; 2002; Nair, 2005; Sun, 2006) ↑ tADC Image Source: Ellingson et al., Concepts in Magn Reson Part A, 2008

5. Spinal Somatosensory Evoked Potentials (SpSEPs) NormalIncomplete SCIComplete SCI Normal SCI No temporal Coherence Loss of Amplitude

6. Experimental Spinal Contusion Impactor Vertebral Body

7. Spinothalamic Tract (STT) & Pain C-fiber input to LSTT (Valeriani, 2007; Li, 1991; Latash, 1988) A  -fiber input to MSTT (Valeriani, 2007; Latash, 1988) Kandel, 2000, Principles of Neural Science

8. Hypothesis Diffusion measurements in the spinothalamic tracts (STTs) correlate with specific components of the SpSEP during high- intensity sciatic nerve stimulation.

9. Methods - Animals Neurologically intact (n = 8) 2 weeks after SCI (n = 8) 5 weeks after SCI (n = 8) Spinal Contusion at T8 (Modified from Baker, 2005)

10. Methods ~ DTI 9.4-T MR Scanner, Embedded in Agarose Gelatin 24 axial images though spinal cord (~7 cm) 6 directions, 100 um resolution Standard Pulsed Gradient Spin-Echo DTI (PG-SE) b = 500 s/mm 2

11. Methods ~ SpSEPs - Animals were anesthetized (Ketamine/Medetomidine IP) -400 V, 10 mA, 3.5 Hz monophasic square wave, pulse duration 500 us -Amplified 20,000x, sampled at 21 kHz, total of 1000 epochs Image source: Ellingson et al., J Neurotrauma, 2008, Under Review

12. Results ~ DTI T2-w lADC

13. Results ~ SpSEPs

14. Results~Correlation DTI and SpSEPs LSTT lADC  Late component (C-fiber) (All animals, R = 0.905, P < 0.001) (2 weeks, R = 0.817, P < 0.01) (5 weeks, R = 0.843, P < 0.01) MSTT lADC  Very Early Component (A  -fiber) (2 weeks, R = 0.812, P < 0.01) (5 weeks, R = 0.841, P < 0.01) Dorsal Columns lADC & tADC  Very Early to Early lADC: VE (2 weeks, R = 0.852, P < 0.01) E (5 weeks, R = -0.718, P < 0.05) tADC: VE (2 weeks, R = 0.792, P < 0.01) E (5 weeks, R = 0.835, P < 0.01)

15. Discussion LSTT lADC  Late component (C-fiber) MSTT lADC  Very Early Component (A  -fiber) Dorsal Columns lADC & tADC  Very Early to Early

16. Future Studies More groups & more specimens Neural stem cells (C17.2) known to cause allodynia  Does lADC & SpSEP amplitude increase beyond control? Prognostic capabilities of DTI  Does DTI predict final neurological outcome? Motor evoked potentials (MEPs)  Is DTI sensitive to motor function deficit?

17. Thank you Brian Schmit, Ph.D. Shekar Kurpad, M.D., Ph.D. Carmen Clark, B.S. James Grosek, B.S. Angie Geiger, B.S. Christy Stadig, B.S. Krishnaj Gourab, M.D. Funding: NIH Falk Foundation Department of Biomedical Engineering, Marquette University Department of Neurosurgery, Radiology, Biophysics at MCW VA Medical Center, Milwaukee WI