1. Diffusion Anisotropy Imaging Shows More Than Just Axonal Connectivity Pratik Mukherjee, MD PhD Associate Professor of Radiology & Bioengineering

2. Mild TBI: the Need for Biomarkers Mild Traumatic Brain Injury (mTBI) Standard clinical measures of injury severity such as GCS, duration of loss of consciousness (LOC), and duration of post-traumatic amnesia (PTA) do not predict the development of persistent PCS, especially in mild TBI A prognostic biomarker for PCS is needed for early patient counseling and for medicolegal purposes A predictive biomarker is needed for triaging patients to interventions as well as for monitoring the effectiveness of the intervention cognitive & occupational rehabilitation cognitive enhancement pharmacotherapy experimental trials of drugs to reduce secondary injury after TBI

3. Diffusion Tensor Imaging Anisotropy (Microstructure): FA: 0 (spherical) to 1 (linear) is CV of DTI eigenvalues Connectivity: Fiber orientation is the primary DTI eigenvector Mukherjee P, et al., AJNR 2008; 29:632-41

4. cingulum bundle superior longitudinal fasciculus centrum semiovale corpus callosum, body 3 Tesla Diffusion Tensor Imaging (DTI) 1.8 mm isotropic spatial resolution

6. Cornell - UCSF Study: 3T MRI-DTI of Mild TBI Is Extent of Microstructural White Matter Injury Related to Global Cognitive Processing Speed? 34 chronic symptomatic mild TBI patients prospectively enrolled 1-65 months after injury, both in NY & SF All with only a single episode of head trauma (predominantly MVAs, assaults, & falls) All with no history of chronic medical or neuropsychiatric illness (including drug or EtOH abuse) All presented with GCS 13-15 in the Emergency Dept. All presented with post-traumatic amnesia All with persistent post-concussive symptoms 26 normal volunteers from NY & SF matched for: age gender handedness years of education Niogi S, Mukherjee P, Ghajar J et al., AJNR 2008; 29:967-73.

7. 3T DTI of Mild TBI Niogi S, Mukherjee P, Ghajar J et al., AJNR 2008; 29:967-73.

8. Spatial Extent of White Matter Injury on DTI Correlates with Cognitive Processing Speed in Mild TBI Niogi S, Mukherjee P, Ghajar J et al., AJNR 2008; 29:967-73.

9. Cornell - UCSF Study: 3T MRI-DTI of Mild TBI Are Attentional and Memory Impairment Related to Damage in Specific White Matter Tracts? 43 chronic symptomatic mild TBI patients prospectively enrolled 1-65 months after injury, both in NY & SF All with only a single episode of head trauma (predominantly MVAs, assaults, & falls) All with no history of chronic medical or neuropsychiatric illness (including drug or EtOH abuse) All presented with GCS 13-15 in the Emergency Dept. All presented with post-traumatic amnesia All with persistent post-concussive symptoms 23 normal volunteers from NY & SF matched for: age gender handedness years of education Niogi S, Mukherjee P, Ghajar J et al., Brain 2008; 131:3209-21.

11. DTI of Blast-Induced Mild TBI

12. Tract-Based Spatial Statistics (TBSS) – Voxel-Wise DTI Analysis using FA Skeletonization Smith, Jenkinson, Johansen-Berg et al. Neuroimage 2006; 31:1487-1505

13. UCSF Prospective Longitudinal Study of Mild TBI with 3T MRI-DTI 31 mild TBI patients prospectively enrolled in Emergency Dept. All with only a single episode of head trauma (predominantly MVAs, assaults, & falls) All with no history of chronic medical or neuropsychiatric illness (including drug or EtOH abuse) All presented with GCS 13-15 in the Emergency Dept. All presented with witnessed loss of consciousness (LOC) All presented with post-traumatic amnesia Patients scanned serially with 3T MRI and DTI at acute (< 2 wks), 1-month, and 1-year time points after injury 30 age-, gender-, & education-matched normal volunteers Yang FG, Manley GT, Mukherjee P et al., ISMRM (2011)

14. Longitudinal DTI of Mild TBI vs Controls: TBSS MD mTBI > controls FA mTBI < controls RD mTBI > controls

15. Longitudinal DTI of Mild TBI vs Controls: TBSS < 2 weeks 1 month 1 year FA(mTBI < controls) P<0.01 P=0

16. Neuroplasticity: Training-Induced Changes in WM Microstructure Scholz et al., Nat Neurosci 2008; 6(7):e159.

17. ICA decomposition for group DTI data Microstructural Correlation Maps Voxel A Y X Noise . + = Subject Localized spatial maps Subject courses Li, Yang, Nguyen, Cooper, LaHue, Venugopal, Mukherjee. Hum Brain Mapp (2011)

18. ICA of Group DTI Data 53 Normal Adult Volunteers: 31 men, 22 women mean age 30.7 ± 8.8 years 44 right-handed supratentorial commissural WM tracts Reproducibility (Rep): measure of algorithmic stability across 30 Monte Carlo trials Percentage Explained Variance (PEV): proportion of total data variance explained by the IC Li, Yang, Nguyen, Cooper, LaHue, Venugopal, Mukherjee. Hum Brain Mapp (2011)

19. ICA of Group DTI Data supratentorial projection WM tracts Li, Yang, Nguyen, Cooper, LaHue, Venugopal, Mukherjee. Hum Brain Mapp (2011).

20. ICA of Group DTI Data neocortical association WM tracts Li, Yang, Nguyen, Cooper, LaHue, Venugopal, Mukherjee. Hum Brain Mapp (2011).

21. Reproducible Quantitative Fiber Tracking: 3T DTI with 55 diffusion directions @ b=1000 CB AF IFO ILF UF CST

22. “Connectomics”: Global Connectivity, not Local Microstructure Hagmann P et al., PLoS Biology 2008; 6(7):e159. Network Metrics Characteristic Path Length Clustering Coefficient Small Worldness Network Efficiency Eigenvector Centrality

23. “Importance Maps”: Loss of Connectivity due to Mild TBI Kuceyeski A et al., Neuroimage 2011; doi:10.1016/jneuroimage.2011.05.087

25. Acknowledgements UCSF Neurosurgery Geoffrey T. Manley, MD PhD Diane Morabito, RN Sara C. LaHue Shelly R. Cooper Hana A. Lee Michele Meeker, RN UCSF Radiology Alisa Gean, MD Fanpei Gloria Yang, PhD Yi-Ou Leo Li, PhD Michael Wahl Joshua Ng Sandya Venugopal, MD Brain Trauma Foundation Jam Ghajar, MD PhD Cornell Sumit N. Niogi, PhD Bruce D. McCandliss, PhD Supported by grants from the McDonnell Foundation, the Dana Foundation, and NIH R01 NS060776 & RC2 NS069409