1. Neuroimaging in Sports-Related Traumatic Brain Injury Inga Katharina Koerte, MD Ross Zafonte, Alexander Lin, Julie Stamm, David Kaufmann, Marc Muehlmann, Michael Mayinger, Karl Helmer, Michael Coleman, Ofer Pasternak, Robert A. Stern, Martha E. Shenton Professor of Neurobiological Research in Child and Adolescent Psychiatriy Department of Child and Adolescent Psychiatry, Psychosomatic, and Psychotherapy, Ludwig-Maximilians-Universität, Munich, Germany Visiting Professor Psychiatry Neuroimaging Laboratory, Brigham and Women‘s Hospital, Harvard Medical School

2. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 2 I have no relevant financial relationships with the products or services described, reviewed, evaluated, or compared in this presentation. Disclosure

3. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 3 1. Neuroimaging of sports-related concussion Impaired function and structure of the brain can be detected and characterized using advanced MRI. 2. Neuroimaging of sports-related subconcussion Advanced MRI makes the invisible visible by detecting brain alterations in the absence of acute symptoms. 3. Future Directions Individual injury profiles, identification of risk factors. Agenda and Key Messages

4. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 4 During a mTBI, the brain undergoes shear deformation producing a stretch of axons alterations in axonal membrane permeability impaired oxidative metabolism energy failure and breakdown of microtubules  Bleeding due to stretch of blood vessels  Edema (swelling of the brain)  Diffuse axonal injury (DAI) Mechanisms of Injury Giza et al. (2001) J Athl Train; Binder et al. (2005) Biochim Biophys Acta; Serbest et al. (2007) Neurochem Res

5. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 5 Multistage Disease Model Koerte and Lin et al. Brain Pathology 2015

6. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 6 Advanced Neuroimaging of Sports-Related Concussion

7. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 7  Bleeding due to stretch of blood vessels  Edema (swelling of the brain)  Diffuse axonal injury (DAI) Neuroimaging of Traumatic Brain Injury Giza et al. (2001) J Athl Train; Binder et al. (2005) Biochim Biophys Acta; Serbest et al. (2007) Neurochem Res; Niogi et al. (2010) J Head Trauma Rehabil, Shenton et al. (2012) Brain Imaging and Behavior  Conventional imaging NOT sensitive for DAI, the most common type of injury in concussion!

8. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 8 In DAI Susceptibility Weighted Imaging (SWI) is 10 times more sensitive to microbleeds than conventional MRI. The number of detected microbleeds in SWI significantly correlates with acute symptoms and long-term outcome in TBI patients. Ashwal et al. (2006) AJNR, Beauchamp et al. (2013) Cortex, Colbert et al. (2010) Radiology, Tong et al. (2003) Radiology, Park et al. (2009) J Korean Neurosurg Soc SWI is Sensitive to Microhemorrhages

9. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 9 Ice hockey players show an increase in hyperintensities following concussion Women had more hyperintensities than men Helmer et al. 2014 Journal of Neurosurgery Hyperintensities During a Play Season

10. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 10 Symptoms and Imaging Findings Resolve Koerte and Lin et al. Brain Pathology 2015

11. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 11 Automated volumetric analysis of cortical and subcortical structures using FreeSurfer Brain Regional Volumetry - T1w MRI Caveat: Most atlases are based on the brains of adults and have to be carefully assessed for quality and potentially be edited Skull-stripped brain Brain segmentation Regional volumes

12. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 12 Former professional, now symptomatic American Football Players (n=71) show  Reduced amygdala volume  Reduced cingulate gyrus volume Hippocampal volume correlated with impaired memory function Volume of cingulate gyrus correlated with severity of depressive symptoms Muehlmann et al. in preparation Brain Volumetry in NFL players

13. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 13 Symptoms and Imaging Findings Resolve Koerte and Lin et al. Brain Pathology 2015

14. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 14 Automated analysis of cortical thickness using FreeSurfer Cortical Thickness Caveat: Interindividual variability can’t be fully appreciated with automated techniques of group analyses Skull-stripped brain Cortical segmentation Differences in cortical thickness

15. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 15 Former professional American football players show  Decrease in cortical thickness with age  This decrease with age is more pronounced than in controls Koerte et al. 2014, IBIA Cortical Thickness in NFL Players

16. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 16 DTI shows Increased FA and decreased MD following acute trauma Decreased FA and increased MD, radial and axonal diffusivity in neurodegenerative processes Microarchitecture of the White Matter - DTI H2OH2O H2OH2O Axonal Loss / Demyelination Axonal Swelling ▲ FA ▼ MD ▼ FA ▲ MD

17. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 17 College ice hockey players show  Increase in trace over the course of a play season  This increase is most pronounced in those with concussion  Most other players also show increase in trace Koerte and Kaufmann et al. J of Neurosurgery 2012 Increased Diffusivity in Ice Hockey Players

18. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 18 Advanced Neuroimaging of Subconcussive Sports- Related Brain Trauma

19. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 19 Soccer is the most popular sport in the world More than 250 Mio active players worldwide 4 Mio registered players in the US (80% below 18 yrs) Figure source: Spiotta et al. 2012 Tysvaer 1981; Ekblom 1986; Matser 1998; Boden 1998; Fuller 2005; Rieder 2011; Tysvaer1992; Tysvaer 1989; Field 2003; Wozniak 2007; Matser 1998; Straume-Naesheim 2005; Witol and Webbe 2003; Stephens 2005; Jordan 1996; McKee 2009; Stern 2011; Guskiewicz 2004; Guskiewicz 2005; Guskiewicz 2007; Guskiewicz 2003; McCrea 2003; Mihalik 2010; Aubry 2002; McCrory 2009; McCrory 2007; Broglio 2012, Zhang 2013 Subconcussive Brain Trauma in Soccer Heading the ball makes soccer unique Unprotected head is a primary point of contact Heading causes forces of up to 60 g 6-12 headings per soccer game

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23. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 23 Soccer is the most popular sport in the world More than 250 Mio active players worldwide 4 Mio registered players in the US (80% below 18 yrs) Figure source: Spiotta et al. 2012 Tysvaer 1981; Ekblom 1986; Matser 1998; Boden 1998; Fuller 2005; Rieder 2011; Tysvaer1992; Tysvaer 1989; Field 2003; Wozniak 2007; Matser 1998; Straume-Naesheim 2005; Witol and Webbe 2003; Stephens 2005; Jordan 1996; McKee 2009; Stern 2011; Guskiewicz 2004; Guskiewicz 2005; Guskiewicz 2007; Guskiewicz 2003; McCrea 2003; Mihalik 2010; Aubry 2002; McCrory 2009; McCrory 2007; Broglio 2012, Zhang 2013 Subconcussive Brain Trauma in Soccer Heading the ball makes soccer unique Unprotected head is a primary point of contact Heading causes forces of up to 60 g 6-12 headings per soccer game Neuropsychological function in soccer players Impaired memory, reduced attention span Controversial results studies Alterations of the brain’s microstructure without symptomatic concussion?

24. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 24 Professional soccer players compared to swimmers:  Increased radial diffusivity of white matter  First prove of microstructural alterations following repetitive subconcussive brain trauma Koerte et al. JAMA 2012 Microarchitecture of White Matter - DTI

25. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 25 Ergebnisse Traktographie

26. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 26 Soc Ctr Soc Ctr * *

27. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 27 Soc Ct r Soc Ctr * *

28. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 28 College football players showed  Increase in trace over the course of a play season in the temporal pole and brain stem  Followed by a decrease during 6 months of non- contact rest Mayinger and Merchant-Brona et al. in preparation Longitudinal WM Changes - DTI

29. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 29 Those with strong hits don’t recover completely Mayinger and Merchant-Brona et al. in preparation Longitudinal WM Changes - DTI

30. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 30 Koerte et al. Brain Imaging and Behavior 2015 Pronounced Cortical Thinning in Soccer Players Former professional soccer players show cortical thinning with age Cortical thickness correlated with exposure to repetitive head impacts

31. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 31 NAA Glx Cr Cho mI Membrane marker Glial marker Energy marker Neurotransmitter Neuronal marker Lin et al. (2012) Brain Imaging and Behavior MR Spectroscopy – The Virtual Biopsy

32. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 32 Alterations in Neurochemistry - MRS Possible neuroinflammation in former professional soccer players Former professional soccer players show increased cholin (membrane marker) and increased myoinositol (glial activation). Metabolites correlate with intensity of exposure to repetitve subconcussive head impacts while heading the ball in soccer. (Koerte and Lin et al., J Neurotrauma 2015)

33. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 33 Future Directions

34. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 34 NFL Control MR Spectroscopy – The Virtual Biopsy Decreased N-acetylaspartate Increased Choline Increased Threonine 2D COSY highly specific Courtesy of Alexander Lin Lin et al. (2012) Brain Imaging and Behavior

35. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 35 Age at first exposure to tackle football  has an effect on the brain’s microstructure  lower FA in CC if training started before age 12 years  the earlier training started the lower FA in CC Stamm, Koerte et al. J Neurotrauma 2015 White Matter Microstructure - DTI

36. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 36 3D normative atlas based on 50 controls Comparison of individual with normative atlas  Individual injury profile Alterations of WM - DTI (Bouix et al., PLOS one 2013)

37. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 37 Concussion and even repetitive subconcussion may lead to alterations of the brain’s structure, metabolism, and function – in some likely reversible, in some maybe not. Underlying mechanisms are not fully understood. Neuroimaging findings indicate neuroinflammation, demyelination, and neurodegeneration. Risk factors need to be identified. Neuroimaging findings suggest age at first exposure, intensity of head impact and/or exposure to repetitive subconcussive brain trauma. Future studies need to include: longitudinal studies to identify risk factors and individual profiles of injury. Summary

38. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 38 Collaborators Ludwig-Maximilians-University Prof. Dr. Maximilian Reiser FACR, FRCR Prof. Birgit Ertl-Wagner David Kaufmann Marc Mühlmann Michael Mayinger Denise Steffinger Barbara Fisch Harvard University Prof. Martha Shenton Prof. Marek Kubicki Prof. Sylvain Bouix Prof. Yogesh Rathi Prof. Alexander Lin Dr. Ofer Pasternak Dr. Maulik Purohit Ryan Eckbo Boston University Prof. Robert Stern Spaulding Rehabilitation Center Prof. Ross Zafonte University of British Columbia, Canada Dr. Paul Echlin Funding: Else Kröner-Fresenius Stiftung Deutscher Akademischer Austauschdienst

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42. AAPM&R, October 1st 2015, Boston Inga Katharina Koerte 42 DTI chatracterizes microstructure Common parameters are calculated using the eigen vectors Fractional Anisotropy (FA): directionality of diffusion Mean Diffusivity (MD): mean diffusion in all directions Radial Diffusivity (RD): diffusion parallel to main axis Axial Diffusivity (AD): diffusion perpendicular to main axis AD = λ1 RD = (λ2 + λ3) / 2 MD = (λ1 + λ2 + λ3) / 3 FA= Diffusion Parameters Basser et al. (1994) Biophys J, Pierpaoli et al. (1996) Radiology