Subconcussive blows: Physiology and Phenotype AAPMR Boston, MA October 1, 2015

1. Subconcussive blows: Physiology and PhenotypeAAPMR Boston, MAOctober 1, 2015 Ross Zafonte,DO Earle P. and Ida S. Charlton Chair and Professor Department of Physical Medicine and Rehabilitation Harvard Medical School Vice President Medical Affairs The Spaulding Rehabilitation Hospital Network Chief Physical Medicine and Rehabilitation Massachusetts General Hospital Brigham and Women’s Hospital RED SOX foundation/MGH Homebase Program

2. Disclosures • None related to this presentation • NIH, NIDLIR, DOD, CIMIT • The Football Players Health Study at Harvard- NFLPA and the Harvard catalyst • Colby College, Maine collaboration • My thanks!!!! • C Giza: UCLA • T McAllister- Indiana

3. Objectives • Definitions • Physiology • Links to phenotype and cautions!

4. Why all the concerns- my bias

5. Sports Concussion ca. 200 B.C. The Iliad - Homer In the battle for Troy, Hector was struck in the head and collapsed, with weakness of the knees and clouding of vision and awareness, but soon recovered and continued to fight. In the end, Hector was killed by Achilles, dragged around Troy behind Achilles’ chariot, and Troy fell to the Greeks..….. was Hector’s performance impaired? C Giza et al

6. Definition of Concussion 2009 • A complex pathophysiological process affecting the brain induced by traumatic biomechanical forces • Marcehetti -1665- alienation of the mind and sense • Due to direct blow or by an ‘impulsive’ force • Clinical symptoms largely reflect dysfunction rather than structural damage • Results in graded set of symptoms, with or without loss of consciousness • Standard structural neuroimaging is normal McCrory P et al., Consensus Statement on Concussion in Sport, (3rd ), Br J Sport Med 2009

7. Subconcussive • Cranial impact that does not result in known or diagnosed concussion on clinical grounds • Slosh effect • Repetitive

8. Parker et al

9. TBI system is the most complicated organ

10. K+ K+ Glutamate Glutamate K+ K+ K+ Neurometabolic Cascade: Potassium & Glutamate Flux Katayama , et.al., J Neurosurg 1990

11. ADP ADP Glutamate Glutamate ATP ATP Glucose Neurometabolic Cascade: Hyperglycolysis and Energy Crisis K+ Pump Energy Crisis!!!

12. Ca2+ Protease activation Glutamate Glutamate Neurometabolic Cascade: Calcium, mitochondrial dysfunction and death Cell Damage/ Death!!! ATP ATP Energy Crisis!!! Mito Glucose For review, see Giza and Hovda, J Athl Training, 2001

13. Inflammation Ca2+ Axonal blebs and swelling Glutamate Impaired axonal transport Microtubule and neurofilament injury Axonal degeneration Neurometabolic Cascade: Axonal Injury Axonal swelling Myelin Damage

14. Human TBI: Abnormal glucose metabolism (PET) Hovda et al GCS 15 GCS 5 GCS 15 Glucose metabolism may show profound abnormalities in humans, even after mild TBI Bergsneider, Hovda, et.al. 2000

15. Initiating Diffuse Axonal Injury: How do Neurons Respond to Mechanical Forces? Reported Neuronal Responses to Mild Mechanical Insults NMDA Channel Activation Metabolic Dysfunction Excitotoxicity Membrane Poration Mechanical Insult Axonal Injury Functional Impairment Acute Ca Influx Mechanotransduction via Cell Adhesion Molecules • Cell adhesion molecules and associated proteins form mechanosensitive structures that sense and respond to cell level forces • Are cellular mechanotransduction mechanisms implicated in initiating axonal injury Matthew Hemphill, Disease Biophysics Group, Harvard University

16. Molecular events in cerebral trauma ONSET 3 h 6 h 0,1 min 1 min 10 min 1,5 h 15 h 5 days 15 days+ ATP [Na+, Ca2+, Cl-] Glutamate Gene expression GET HSP Inflammation Proteases Remodeling

17. Repeated exposures Glushkova et al • Increasing recovery time between injuries improves cognitive outcome after repetitive mild concussive brain injuries in mice • Meehan et al Neurosurgery 2012 • Repetitive mild mTBI causes changes in cortical and hippocampal cytosketal protein • Kanayama et al 1996

18. 1 . 6 Control/STD * 1 . 5 FP/STD Sham/EE 1 . 4 FP/EE 1 . 3 1 . 2 1 . 1 FP/EE 1 . 0 Sham/STD Sham/EE Group Dendritic reconstruction Average Smarter after EE Average after trauma and EE Ip, et.al., J Neurotrauma, 2002 Is Younger Better…or Not? Loss of Experience-Dependent Plasticity Cortical thickness Cortical thickness and dendritic arborization increase in response to Enriched Environment. Environment-induced structural brain enhancements were NOT seen after developmental TBI. ?? Age of First exposure – Shaim et al Neurology 2014 Occipital Cortical thickness (mm) Fineman, Giza, et.al., J Neurotrauma, 2000

19. Exposure(n=254, Impacts = 184,000) high strain forces deep midbrain 10msec following ~500 -1500 impacts per season Is it also the force? HUGE CAVEATS McAllister et al 2014 3000 hits over 4 years of high school ~5000 hits over 4 years of college ~8000 total over 8 year “career” Adapted from Broglio et al.(2011) J of Neurotrauma

20. Cumulative impact by force and level Skill versus Force positions OL- 20-30 g on almost every play Schnebel et al Neurosurgery 2007 Bailes et al Neurosurgery 2013

21. Subconcussive blows Talavage et al J Neurotrauma 2014 11 young men High number of collisions Visual working memory and DLPC change

22. Traumatic Brain Injury Pathophysiology – a continuum of biomarkers Subacute Biomarkers (MAP2, SBDP120, MBP) Chronic Neuro-response Biomarkers (BA-0293, BA0296, BA-0297) Acute Biomarkers (UCH-L1, GFAP, SBDP150) Injury Necrosis Wang et al Axonal Injury Apoptosis Gliosis [Protein Biomarker] blood Demyelination Chronic neuro-responses Microgliosis Min Hr Days Weeks Months 22

23. Biomarkers • Professional ice hockey Players in Sweden • 47 players – 35 with concussion • total tau** • S-100b • NSE Total tau Shaim JAMA Neurology 2014

24. CTE Hallmark Feature: Tau ProteinBrown = stained for TauNormal brain should have no brown McKee et al Depths of sulci and perivascular First described in boxers by Martland in 1928

25. Tauopathy Castellani et al Neurosurgery 2015

26. cis tau-induced cistauosis could be a mechanism in TBI and its neurodegeneration Tangles Severe TBI (blast or impact) CTE AD “cistauosis” Axonopathy LTP defects Neuron death Disease spread Brain dysfunction Brain atrophy Localized to axons cis p-tau levels Repeated concussions Kondo et al., Nature 2015 Concussion) 0 12 hr 2 weeks Months Years later “Over the past 70 years, diffuse axonal injury (DAI) has emerged as one of the most common and important pathological features of traumatic brain injury (TBI)” (Douglas Smith, 2012, ExpNeurol)

27. Progressive theory Smith D. Nature Neurosci 2014

28. Large studies: not in sport Dementia risk Parkinsons disease risk Among those >55 52,393 TBI 113,406 NTT PD more likely in those with TBI 44% increased risk of developing TBI in 5-7 years • Retrospective cohort study • 51,799 patients with trauma—31.5% with TBI • 8.4% with TBI dementia • 5.9% NTT dementia • > age 65-74 greatest risk Gardner et al JAMA Neurology 2014 Gardner et al. Ann Neurology 2015

29. Disturbances: The Phenotype? Arciengas D, Silver J. Pharmacotherapy of neuropsychiatric disturbances, in Brain Injury Medicine: Principles and Practice. Edited by Zasler ND, Katz DI, Zafonte RD.

30. Summary • Little level 1 evidence to guide us • More injury is bad but how bad and in whom? • at what threshold • how close together • how is this linked or not to long term symptoms • Detection of structural dysfunction may come before long term outcome and phenotypic association!

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