Penn Center for Brain Injury and Repair<br />Known knowns and known unknowns:A “disconnect” – Is there Axonal Pathology Fo...
No personal attacks are intended!<br />3.3 lb. Human Brain<br />1 lb. Boxing Glove<br />
It is generally believed that<br />diffuse axonal injury is the<br />primary neuropathologicalsequelae<br />of non-blast m...
Contact Loading<br />Inertial Loading<br />1o BLAST?<br />Diffuse Axonal Injury (DAI)<br />
Diffuse Axonal Injury<br />Inertial loading<br />
DAI: Diagnosis of exclusion<br />T2<br />CT<br /> A “disconnection” syndrome<br />
Evolution of Axonal Pathology<br />Periodic varicosities<br />Terminal bulb<br />
Axonal Pathologies Post-trauma<br />
What is DAI?<br />“A diffuse degeneration of the white matter of the cerebral hemispheres.”<br />“there is much evidence i...
<ul><li> Correlated with angular acceleration model in non-human primate1-3. </li></ul>1. (Genarelli, TA et al Ann. Neurol...
What breaks in the brain during<br />Non-blast TBI?<br />Modeling based on<br />human neuropathology<br />
“All models are wrong.Some are useful”<br />George Box, 1979<br />
HYGE<br />Pneumatic actuator<br />
Inertial Brain Injury in the Pig<br />Deceleration<br />Pre-Acceleration<br />Acceleration<br />
DAI is the source of immediate loss of consciousness and coma<br />Following non-blast<br />brain trauma<br />
40-<br />axial<br />coronal<br />20-<br />min<br />LOC<br />Mild TBI<br />
Tensile elongation of axons<br />
Culture Axonal Injury (CAI)<br />
Glu<br />Tyr<br />
In vivo strain gauge after head<br />Would this occur in blast TBI?<br />18 y/o F  MVA <br />22h survival<br />Adult Pig 3...
MT twisting<br />      &<br />breakage<br />
Stretch injury triggers microtubule instability<br />
APP<br />18 y/o M<br />Assault<br />10 h survival<br />Mechanical failure of axonal cytoskeleton <br />may be unique to TB...
Undulations<br />Varicosities<br />Bulbs<br />together in acute/<br />subacute human<br />non-blast TBI<br />
Pre-injury<br />Post-injury<br />3% strain<br />5% strain<br />20% strain<br />Strain-dependent threshold for calcium infl...
NaChimmunoreactivity<br />Pre-injury<br />1hr post-injury<br />24hr post-injury<br />Posttraumatic increase in NaCh densit...
Human blast TBI pathology<br />
Scientistswould rather<br />share atoothbrushthan use<br />each other’s paradigms<br />Poor consensus for animal models of...
bTBI animal models:<br />is there DAI as seen<br />in non-blast TBI?<br />
Shock Tube Testing(Penn & NMRC)<br />WRAIR/ NMRC shocktube<br />
Photonic Nanocrystals in Nature<br />
Exploit Mechanical Failure<br />of Photonic Crystals<br />Crystal Failure<br />Sonic Blast<br />
Blast Injury Dosimeter ArraysTested at NMRC<br />
Blast Injury Dosimeter<br />pre-blast<br />post-blast<br />
Gross Pathology<br />Shockwave peak overpressure 120 – 140 kPa<br />
Neuronal Degeneration<br />
Reactive Astrocytosis<br />
Axonal Pathology<br />Sham 		            Blast (24hr)    		       FPI<br />APP<br />NF 200<br />
Silver Staining (Cortex, 120 kPa)<br />24hrs<br />sham<br />48hrs<br />3hrs<br />4x<br />20x<br />
Silver Staining (120 kPa)<br />sham<br />24hrs<br />48hrs<br />DG<br />10x<br />CC<br />20x<br />
Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae.<br />Levin HS, et al.<...
Classic silver staining of axonal pathology<br />Deep white matter<br />Classic silver staining of axonal pathology<br />C...
Decreased Axonal but Increased PerikaryalPhosphorylated Neurofilament Heavy (p-NFH)<br />SHAM<br /><ul><li>pentaerythritte...
Whole Body Lateral Exposure
No Gross Pathology
p-NFH changes last up to 7d
Axonal transport disruption?</li></ul>Post-BLAST (18Hr)<br />Post-BLAST (18Hr)<br />SÄLJÖ, A; BAO, F; HAGLID, KG; HANSSON,...
Amyloid Precursor Protein<br />21d POST-BLAST (CTX - RAT)<br />SÄLJÖ, A; BAO, F; SHI, J; HAMBERGER, A; HANSSON, H-A; HAGLI...
Silver Stain: Moderate Charge Exposed to Swine within a Building<br />Baumen, RA et al. J Neurotrauma; 26:841–860 (June 20...
Silver Stain: Moderate Charge Exposed to Swine within a Building<br />Ipsilateral <br />Frontal CTX<br />Baumen, RA et al....
Blast Overpressure Generated using  compression-driven shock tube<br />Long, JB et al. J Neurotrauma; 26:827–840 (June 200...
Long, JB et al. J Neurotrauma; 26:827–840 (June 2009)<br />
Corpus Callosum (APP)<br />CerebellarPeduncle:Gallyas Silver Stain<br />Gallyas Silver Stain<br />Koliatsos, VE et al.<br ...
“Exposure in the blast tube did not induce DAI” <br />Mechanisms of blast induced brain injuries, experimental studies in ...
EFFECT OF BLAST EXPOSURE ON THE BRAIN<br />STRUCTURE AND COGNITION IN THE MACACA FASCICULARIS<br />JiaLU et al., J. Neurot...
Microglial Activation and Astrocytosis Following Blast-Injury (Rat)<br />Microglia (OX-42) in CA1<br />GFAP in CA1<br />SH...
Microglial Activation Following exposure of Rats to Air-Driven Shock-Tube<br />Readnower RD et al, J Neurosci Re; 88;3530-...
Moderate Charge Exposed to Swine within a Building<br />GFAP (superior corona radiata)<br />Ipsilateral<br />Contralateral...
EFFECT OF BLAST EXPOSURE ON THE BRAIN<br />STRUCTURE AND COGNITION IN THE MACACA FASCICULARIS<br />JiaLU et al., J. Neurot...
Hemorrhage?<br />No hemorrhage<br />Intraparenchymal bleeding<br />Subarachnoid hemorrhage<br />Subdural hemorrhage<br />C...
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Smith, Doug H.

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Smith, Doug H.

  1. 1. Penn Center for Brain Injury and Repair<br />Known knowns and known unknowns:A “disconnect” – Is there Axonal Pathology Following Blast TBI?<br />Douglas H. Smith, MD<br />Department of Neurosurgery and<br />Penn’s Center for Brain Injury and Repair<br />University of Pennsylvania<br />
  2. 2. No personal attacks are intended!<br />3.3 lb. Human Brain<br />1 lb. Boxing Glove<br />
  3. 3. It is generally believed that<br />diffuse axonal injury is the<br />primary neuropathologicalsequelae<br />of non-blast mTBI/ concussion.<br />Is this true in mild blast TBI as well? <br />
  4. 4. Contact Loading<br />Inertial Loading<br />1o BLAST?<br />Diffuse Axonal Injury (DAI)<br />
  5. 5. Diffuse Axonal Injury<br />Inertial loading<br />
  6. 6. DAI: Diagnosis of exclusion<br />T2<br />CT<br /> A “disconnection” syndrome<br />
  7. 7. Evolution of Axonal Pathology<br />Periodic varicosities<br />Terminal bulb<br />
  8. 8. Axonal Pathologies Post-trauma<br />
  9. 9. What is DAI?<br />“A diffuse degeneration of the white matter of the cerebral hemispheres.”<br />“there is much evidence in favour of mechanical damage as the chief cause for the lesions”<br />Strich, SJ:Lesions in the cerebral hemispheres after blunt head injury. J ClinPatholSuppl (R CollPathol). 1970; 4: 166–171. <br />
  10. 10. <ul><li> Correlated with angular acceleration model in non-human primate1-3. </li></ul>1. (Genarelli, TA et al Ann. Neurol. 1982; 12; 564-574. 2. Genarelli, TA et al Society of Automotive Engineers, 1987; 49-53. 3. Generallii, TA et al New York: Plenum Press, 1986; 15-28.<br />
  11. 11. What breaks in the brain during<br />Non-blast TBI?<br />Modeling based on<br />human neuropathology<br />
  12. 12. “All models are wrong.Some are useful”<br />George Box, 1979<br />
  13. 13. HYGE<br />Pneumatic actuator<br />
  14. 14. Inertial Brain Injury in the Pig<br />Deceleration<br />Pre-Acceleration<br />Acceleration<br />
  15. 15.
  16. 16. DAI is the source of immediate loss of consciousness and coma<br />Following non-blast<br />brain trauma<br />
  17. 17. 40-<br />axial<br />coronal<br />20-<br />min<br />LOC<br />Mild TBI<br />
  18. 18. Tensile elongation of axons<br />
  19. 19. Culture Axonal Injury (CAI)<br />
  20. 20.
  21. 21.
  22. 22. Glu<br />Tyr<br />
  23. 23. In vivo strain gauge after head<br />Would this occur in blast TBI?<br />18 y/o F MVA <br />22h survival<br />Adult Pig 3 h survival<br />18 y/o M Assault <br />10 h survival<br />
  24. 24. MT twisting<br /> &<br />breakage<br />
  25. 25. Stretch injury triggers microtubule instability<br />
  26. 26. APP<br />18 y/o M<br />Assault<br />10 h survival<br />Mechanical failure of axonal cytoskeleton <br />may be unique to TBI<br />
  27. 27. Undulations<br />Varicosities<br />Bulbs<br />together in acute/<br />subacute human<br />non-blast TBI<br />
  28. 28. Pre-injury<br />Post-injury<br />3% strain<br />5% strain<br />20% strain<br />Strain-dependent threshold for calcium influx with TAI<br />
  29. 29. NaChimmunoreactivity<br />Pre-injury<br />1hr post-injury<br />24hr post-injury<br />Posttraumatic increase in NaCh density = NaChO?<br />
  30. 30. Human blast TBI pathology<br />
  31. 31.
  32. 32. Scientistswould rather<br />share atoothbrushthan use<br />each other’s paradigms<br />Poor consensus for animal models of non-blast TBI.<br />Blast TBI models – <br />far less consensus<br />
  33. 33. bTBI animal models:<br />is there DAI as seen<br />in non-blast TBI?<br />
  34. 34. Shock Tube Testing(Penn & NMRC)<br />WRAIR/ NMRC shocktube<br />
  35. 35. Photonic Nanocrystals in Nature<br />
  36. 36. Exploit Mechanical Failure<br />of Photonic Crystals<br />Crystal Failure<br />Sonic Blast<br />
  37. 37. Blast Injury Dosimeter ArraysTested at NMRC<br />
  38. 38. Blast Injury Dosimeter<br />pre-blast<br />post-blast<br />
  39. 39. Gross Pathology<br />Shockwave peak overpressure 120 – 140 kPa<br />
  40. 40. Neuronal Degeneration<br />
  41. 41. Reactive Astrocytosis<br />
  42. 42. Axonal Pathology<br />Sham Blast (24hr) FPI<br />APP<br />NF 200<br />
  43. 43. Silver Staining (Cortex, 120 kPa)<br />24hrs<br />sham<br />48hrs<br />3hrs<br />4x<br />20x<br />
  44. 44. Silver Staining (120 kPa)<br />sham<br />24hrs<br />48hrs<br />DG<br />10x<br />CC<br />20x<br />
  45. 45. Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae.<br />Levin HS, et al.<br />J Neurotrauma. 2010 Apr;27(4):683-94<br />“Our data do not show WM injury in mild to moderate blast-related TBI in veterans despite their residual symptoms and difficulty in verbal memory”<br />
  46. 46. Classic silver staining of axonal pathology<br />Deep white matter<br />Classic silver staining of axonal pathology<br />Corpus callosum and internal capsule after<br />Non-blast TBI<br />Classic silver staining of non-blast DAI for comparison<br />
  47. 47. Decreased Axonal but Increased PerikaryalPhosphorylated Neurofilament Heavy (p-NFH)<br />SHAM<br /><ul><li>pentaerythrittetranitrate (240,KPa.)
  48. 48. Whole Body Lateral Exposure
  49. 49. No Gross Pathology
  50. 50. p-NFH changes last up to 7d
  51. 51. Axonal transport disruption?</li></ul>Post-BLAST (18Hr)<br />Post-BLAST (18Hr)<br />SÄLJÖ, A; BAO, F; HAGLID, KG; HANSSON, H-A. (2000). J Neurotrauma; Vol 17:18.719-728<br />
  52. 52. Amyloid Precursor Protein<br />21d POST-BLAST (CTX - RAT)<br />SÄLJÖ, A; BAO, F; SHI, J; HAMBERGER, A; HANSSON, H-A; HAGLID, KG. (2002)J Neurotrauma<br />Vol 19, Issue 3, Pg 105-111 <br />
  53. 53. Silver Stain: Moderate Charge Exposed to Swine within a Building<br />Baumen, RA et al. J Neurotrauma; 26:841–860 (June 2009)<br />
  54. 54. Silver Stain: Moderate Charge Exposed to Swine within a Building<br />Ipsilateral <br />Frontal CTX<br />Baumen, RA et al. J Neurotrauma; 26:841–860 (June 2009)<br />
  55. 55. Blast Overpressure Generated using compression-driven shock tube<br />Long, JB et al. J Neurotrauma; 26:827–840 (June 2009)<br />
  56. 56. Long, JB et al. J Neurotrauma; 26:827–840 (June 2009)<br />
  57. 57. Corpus Callosum (APP)<br />CerebellarPeduncle:Gallyas Silver Stain<br />Gallyas Silver Stain<br />Koliatsos, VE et al.<br /> J Neuropathol Exp Neurol. 70;5;399-416, 2011<br />
  58. 58. “Exposure in the blast tube did not induce DAI” <br />Mechanisms of blast induced brain injuries, experimental studies in rats.<br />Risling et al.Neuroimage. 2011:S89-97.<br />
  59. 59. EFFECT OF BLAST EXPOSURE ON THE BRAIN<br />STRUCTURE AND COGNITION IN THE MACACA FASCICULARIS<br />JiaLU et al., J. Neurotrauma, in press<br />No DAI reported, but apparent demyelination, disorganized myelin, vaculoes<br />and loss of structure <br />MBP<br />EM<br />
  60. 60. Microglial Activation and Astrocytosis Following Blast-Injury (Rat)<br />Microglia (OX-42) in CA1<br />GFAP in CA1<br />SHAM<br />SHAM<br />7d Post BLAST<br />21d Post BLAST<br />SÄLJÖ, A; BAO, F; HAMBERGER, A; HAGLID, KG; HANSSON, H-A. (2001). Pathophysiology<br />Vol 8, Issue 2, Pg 105-111 <br />
  61. 61. Microglial Activation Following exposure of Rats to Air-Driven Shock-Tube<br />Readnower RD et al, J Neurosci Re; 88;3530-3539<br />
  62. 62. Moderate Charge Exposed to Swine within a Building<br />GFAP (superior corona radiata)<br />Ipsilateral<br />Contralateral<br />Baumen, RA et al. J Neurotrauma; 26:841–860 (June 2009)<br />
  63. 63. EFFECT OF BLAST EXPOSURE ON THE BRAIN<br />STRUCTURE AND COGNITION IN THE MACACA FASCICULARIS<br />JiaLU et al., J. Neurotrauma, in press<br />S100ß<br />
  64. 64. Hemorrhage?<br />No hemorrhage<br />Intraparenchymal bleeding<br />Subarachnoid hemorrhage<br />Subdural hemorrhage<br />Cortical Contusion<br />Microbleeds –Capillary leakage<br />Chen, J et al Journal of the Neurological Sciences 294 (2010) 23–28 <br />Kado et al. JNeurosurg 106:667–676, 2007 <br />SÄLJÖ, A. J Neurotrauma; 25:1397–1406 (2008)<br />
  65. 65. TBI modeling<br />Non-blast axonal pathology:<br />-Microtubule breakage<br /><ul><li>Undulations
  66. 66. Ionic fluxes
  67. 67. Acute/ Chronic channelopathy
  68. 68. Transport interruption
  69. 69. Swellings (varicosities and bulbs)
  70. 70. Wallerian degeneration</li></ul>Blast axonal pathology:<br />-limited axonal swellings<br />-darker silver and IHC staining<br /> of brain regions<br />-myelin changes?<br />-as yet undetected type of<br />subcellular damage?<br />
  71. 71. Blast TBI Models:<br />Hemorrhage – not found in clinical blast mTBI<br />No strong evidence of extensive DAI/ TAI<br />Modest neuronal degeneration<br />Uniform inflammation across models<br />Does not fit current hypotheses<br />of mild bTBI in humans<br />
  72. 72. Are swollen axons the predominant pathology of DAI?<br />
  73. 73. Acknowledgements<br /><ul><li>D. Kacy Cullen, Ph.D., Victoria Johnson, and Kevin Browne, B.S., Dept. of Neurosurgery, Univ. of Pennsylvania
  74. 74. Shu Yang, Ph.D., and YonganXu, Ph.D., Materials Science and Engineering, Univ. of Pennsylvania
  75. 75. James Geddes, Ph.D., Univ. of Kentucky
  76. 76. MikulasChavko, Ph.D., and Richard M. McCarron, Ph.D., Naval Medical Research Center
  77. 77. Funding: NIH (NS38104) and Nanotechnology Institute (NTI)</li>

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