Neuroimaging in Sports-Related Traumatic Brain Injury

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. Disclosure • I have no relevant financial relationships with the products or services described, reviewed, evaluated, • or compared in this presentation.

3. Agenda and Key Messages • 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.

4. Mechanisms of Injury • 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) • Giza et al. (2001) J Athl Train; Binder et al. (2005) Biochim Biophys Acta; Serbest et al. (2007) Neurochem Res

5. Multistage Disease Model Koerte and Lin et al. Brain Pathology 2015

6. Advanced Neuroimaging of Sports-Related Concussion

7. Neuroimaging of Traumatic Brain Injury • Bleeding due to stretch of blood vessels • Edema (swelling of the brain) • Diffuse axonal injury (DAI)  Conventional imaging NOT sensitive for DAI, the most common type of injury in concussion! • 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

8. SWI is Sensitive to Microhemorrhages • 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

9. Hyperintensities During a Play Season • Ice hockey players show an increase in hyperintensities following concussion • Women had more hyperintensities than men Helmer et al. 2014 Journal of Neurosurgery

10. Symptoms and Imaging Findings Resolve Koerte and Lin et al. Brain Pathology 2015

11. Brain Regional Volumetry - T1w MRI • Automated volumetric analysis of cortical and subcortical structures using FreeSurfer Regional volumes Brain segmentation Skull-stripped brain • Caveat: • Most atlases are based on the brains of adults and have to be carefully assessed for quality and potentially be edited

12. Brain Volumetry in NFL players • 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

13. Symptoms and Imaging Findings Resolve Koerte and Lin et al. Brain Pathology 2015

14. Cortical Thickness Automated analysis of cortical thickness using FreeSurfer Differences in cortical thickness Cortical segmentation Skull-stripped brain • Caveat: • Interindividual variability can’t be fully appreciated with automated techniques of group analyses

15. Cortical Thickness in NFL Players • 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

16. H2O H2O Microarchitecture of the White Matter - DTI • DTI shows • Increased FA and decreased MD following acute trauma • Decreased FA and increased MD, radial and axonal diffusivity in neurodegenerative processes Axonal Loss / Demyelination Axonal Swelling ▲ FA ▼ FA ▲ MD ▼ MD

17. Increased Diffusivity in Ice Hockey Players • 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

18. Advanced Neuroimaging of Subconcussive Sports-Related Brain Trauma

19. 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 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

23. 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 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 Alterations of the brain’s microstructure without symptomatic concussion? 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

24. Microarchitecture of White Matter - DTI • 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

25. Ergebnisse Traktographie

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28. Longitudinal WM Changes - DTI • 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

29. Longitudinal WM Changes - DTI • Those with strong hits don’t recover completely Mayinger and Merchant-Brona et al. in preparation

30. Pronounced Cortical Thinning in Soccer Players • Former professional soccer players show cortical thinning with age • Cortical thickness correlated with exposure to repetitive head impacts Koerte et al. Brain Imaging and Behavior 2015

31. MR Spectroscopy – The Virtual Biopsy Choline Creatine N-acetyl aspartate Energy marker Myo-inositol Neuronal marker NAA Membrane marker Cr Glutamate Glial marker Cho Glx mI Neurotransmitter Lin et al. (2012) Brain Imaging and Behavior

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. Future Directions

34. MR Spectroscopy – The Virtual Biopsy • Decreased N-acetylaspartate • Increased Choline • Increased Threonine • 2D COSY highly specific Control NFL Courtesy of Alexander Lin Lin et al. (2012) Brain Imaging and Behavior

35. White Matter Microstructure - DTI • 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

36. Alterations of WM - DTI • 3D normative atlas based on 50 controls • Comparison of individual with normative atlas • Individual injury profile (Bouix et al., PLOS one 2013)

37. Summary • 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.

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 Spaulding Rehabilitation Center • Prof. Ross Zafonte Boston University • Prof. Robert Stern University of British Columbia, Canada • Dr. Paul Echlin Funding: Else Kröner-Fresenius Stiftung Deutscher Akademischer Austauschdienst

39. Thank you for your attention! Please visit our website: http://pnl.bwh.harvard.edu

40. BACKUP

42. DTI chatracterizes microstructure Diffusion Parameters • 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 FA = MD = (λ1 + λ2 + λ3) / 3 RD = (λ2 + λ3) / 2 AD = λ1 Basser et al. (1994) Biophys J, Pierpaoli et al. (1996) Radiology