1. David A. Hovda, Ph.D. Director, UCLA Brain Injury Research Center Professor of Neurosurgery Molecular and Medical Pharmacology David Geffen School of Medicine at UCLA WWW.BIRC.UCLA.EDU 2011 National Neurotrauma Conference Hollywood Beach, FL July 13, 2011 Mechanisms of Concussion Funded by: NS02197, NS27544, NS052406 UC Neurotrauma Initiative, UCLA Faculty Grant Program and the Lind Lawrence Foundation. NOTHING TO DISCLOSE
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3. EVERY TBI STARTS OUT AS A CONCUSSION What is so mild about mild traumatic brain injury? Walker, A.E et al, 1944; The physiological basis of concussion. J. Neurosurgery, 1: 103-166
4. Constantin van Monakow 1853-1930 Swiss Neurologist of Russian Extraction Diaschisis To distinguish between the transient central nervous disorders due to suppression of brain activity and the deficits resulting from brain lesions that never disappear.
9. Neurometabolic Cascade: Calcium, mitochondrial dysfunction and death ATP Glucose Energy Crisis!!! Mito Cell Damage/ Death!!! ATP For review, see Giza and Hovda, J Athl Training, 2001 Ca2+ Protease activation Glutamate Glutamate
10. Neurometabolic Cascade: Axonal Injury Axonal swelling Myelin Damage Axonal blebs and swelling Microtubule and neurofilament injury Impaired axonal transport Axonal degeneration Ca2+ Inflammation Glutamate
11. Neurometabolic Cascade: Now we can see it Energy Crisis Mito PET, MRS Protein Biomarkers? Cell Damage/ Death Protease activation MRI Axonal injury DTI Altered neurotrans-mission Glutamate fMRI
12. McAllister, et al. Neurology, 1999 Human mTBI: Impaired Activation (fMRI) Mildly injured individuals demonstrate abnormal activation patterns during a more difficult working memory task. Mild TBI patients (GCS 13-15), n=12; controls n=11 Average time of testing was 22.1 ± 10.5 days after TBI. Loss of consciousness: 1 to 30 min. Post-traumatic amnesia: 15 min to 24 hrs. % correct mTBI control 0-back 95.1 96.2 1-back 95.8 95.5 2-back 81.0 89.4 No significant differences Mild TBIs Controls
13. Human mTBI: Abnormal axons (DTI) Wilde E, et.al. Neurology, 2008 In adolescents with mTBI, DTI of the CC performed within 6 days showed increased FA and decreased diffusivity. These abnormalities in DTI correlated well with post-concussion symptoms.
17. Human mTBI: Altered metabolism (MRS) Vagnozzi, et.al. Neurosurgery, 2008 Single concussion Double concussion There were significant reductions of NAA/Cr for 30 days after 1 concussion and 45 days after 2 concussions. Vagnozzi, et.al. Brain, 2010
18. GLUCOSE GLUCOSE LACTATE LACTATE C P C M C E G-6-P BBB brain capillary endothelial cytoplasm PYRUVATE PYRUVATE ACETYL-CoA TCA CO 2 H 2 O k 1 k 3 k 2 Pentose Shunt GLYCOGEN GLYCOGEN – ~97% ~13% Amino Acids ~5% GLUCOSE G-6-P G-1-P PYRUVATE LACTATE hexokinase ASTROCYTE NEURON 2 ATPs 36 ATPs Oxygen/ Glucose Ratio 1 Glucose:5.6 parts Oxygen 5.6 Oxygen G1 G1 G3 G1 G1 G1 G1 MCT MCT MCT MCT MCT hexokinase glucose-6- phosphatase
22. Metabolic Priorities After Traumatic Brain Injury The role for Glucose and Lactate had Changed! Astrocytes may need help! Bartnik et al. J Neurotrauma 2005, 2007a,b Dusick et al. J Cereb Blood Flow Metab 2007
28. The UCLA Brain Injury Research Center Basic Scientists Chris Giza, M.D. Fernando Gomez-Pinilla, Ph.D. Grace Griesbach, Ph.D. Neil Harris, Ph.D. Mayumi Prins, Ph.D. Richard Sutton, Ph.D. Graduate Students Gretchen Miller. Maxine Reger Naomi Santa Maria Derek Verley Lab Assistants Yan Cai, M.S. Sima Ghavim Nurses Maria Etchepare Sue Yudovin Clinical Investigators Thomas Glenn, Ph.D. Neil Martin, M.D. Paul Vespa, M.D. Marvin Bergsneider, M.D Robert Asarnow, M.D. Andy Madikians, M.D. David McArthur, Ph.D M.P.H. Michelle van Hirtum-Das, M.D. Talin Babikian, Ph.D. Funded by: NS02197, NS27544, NS052406 UC Neurotrauma Initiative, UCLA Faculty Grant Program and the Lind Lawrence Foundation. www.birc.ucla.edu Post Doctoral Fellows Sarah Copeland, M.D. Ph.D. Nobouhiro Moro, M.D., Ph.D Katsunori Shijo, M.D., Ph.D.