A Murine Model of Multiple Mild Concussive Brain Injuries and the Effects of Recovery Time on Cognitive Outcome<br />Bill ...
Nathan Horton was concussed.  <br />
Mechanism and Definition<br />Rotational Acceleration <br />Denny-Brown & Russell, Brain, 1941<br />Ommaya & Genarelli, Br...
Extent of the problem<br />CDC: As many as 3.8 million sport-related TBIs per year in US (MMWR 2007;56(29):733-737)<br />A...
Research questions<br />Are the cognitive effects of multiple concussions cumulative?<br />Can the cognitive effects of mu...
Criteria for model development<br />Rotational acceleration<br />Cognitive dysfunction without gross structural damage<br ...
Methods<br />Adult (12-16 weeks) male C57BL/6 mice <br />Modified weight drop model (DeFord, et al. J Neurotrauma, 2002)<b...
Methods<br />Gross examination of skull and brain<br />Edema assessment: wet-dry weight method<br />Immunohistochemistry: ...
Methods<br />Morris water maze hidden platform trials<br />5 trials, each consisting of 4 sub-trials, 1 per quadrant<br />...
No Structural Injury<br /><ul><li>LOC    42”:      120.0 ± 20.8; </li></ul> 	     38”:      104.9 ±14.9; <br /> 	     Sham...
 No intracranial hemorrhage
 No contusion
No cerebral edema</li></ul>    (77.5 ± 0.1 vs. 77.3 ± 0.4 %) <br />
CCI<br />Our model<br />Fluoro-Jade B<br />APP      <br />(axon injury)<br />TUNEL <br />Anti-mouse IgG<br />Results: Hist...
 Hippocampus
 Thalamus
 Corpus callosum
 Brain stem</li></li></ul><li>Morris Water Maze<br />OneConcussion<br />ThreeConcussions<br />Trial #<br />Trial #<br />(p...
Research Question 1<br />Are the cognitive effects of multiple concussions cumulative?  <br />YES<br />
5 Weekly Concussions<br />5 Daily Concussions<br />Trial #<br />Trial #<br />5 Monthly Concussions<br />Trial #<br />(p=0....
Research Question 2<br />Can the cognitive effects of multiple concussions be diminished by increasing the time interval b...
5 Daily Concussions<br />One Month Later<br />Trial #<br />Trial #<br />(p=0.01, 5 mice per group)<br />(p=0.01, 5 mice pe...
5 Weekly Concussions<br />Trial #<br />One Month After Final Injury<br />One Month Later<br />Trial #<br />(p=0.07, 7 mice...
One Month Later<br />One Month Later<br />Trial #<br />Trial #<br />(p=0.21, 5 sham, 4 from 42”, 8 from 38”)<br />5 Monthl...
One Year Later<br />5 Daily Concussions<br />One Year Later<br />One Year Later<br />Trial #<br />Trial #<br />Trial #<br ...
Upcoming SlideShare
Loading in …5
×

Meehan, William

510 views

Published on

Published in: Health & Medicine, Technology
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
510
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
0
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Meehan, William

  1. 1. A Murine Model of Multiple Mild Concussive Brain Injuries and the Effects of Recovery Time on Cognitive Outcome<br />Bill Meehan, MD<br />Sports Concussion Clinic<br />Children’s Hospital Boston<br />Neuroscience Center<br />Massachusetts General Hospital<br />Support<br />NIH: T32 HD040128-06A1 <br />National Football League Charities Foundation<br />
  2. 2.
  3. 3.
  4. 4.
  5. 5.
  6. 6.
  7. 7.
  8. 8.
  9. 9. Nathan Horton was concussed. <br />
  10. 10. Mechanism and Definition<br />Rotational Acceleration <br />Denny-Brown & Russell, Brain, 1941<br />Ommaya & Genarelli, Brain, 1974<br />Concussion Definition<br />A disturbance of neurological function rather than a structural injury <br />International Consensus on Concussion in Sports 2009<br />
  11. 11. Extent of the problem<br />CDC: As many as 3.8 million sport-related TBIs per year in US (MMWR 2007;56(29):733-737)<br />Acutely: cognitive dysfunction, headaches, insomnia, depression<br />After years: cognitive dysfunction, dementia, psychological disorders, increased risk of suicide<br />Chronic Traumatic Encephalopathy<br />
  12. 12. Research questions<br />Are the cognitive effects of multiple concussions cumulative?<br />Can the cognitive effects of multiple concussions be alleviated by increasing the time interval between injuries? <br />
  13. 13. Criteria for model development<br />Rotational acceleration<br />Cognitive dysfunction without gross structural damage<br />No cell death, edema, hematoma; dissociate effects of concussion from structural lesions<br />Cumulative effects of multiple, mild injuries<br />Explore the concept of recovery period<br />
  14. 14. Methods<br />Adult (12-16 weeks) male C57BL/6 mice <br />Modified weight drop model (DeFord, et al. J Neurotrauma, 2002)<br />Sham injured mice anesthetized only<br />54 g weight, variable drop height (42in, 38in)<br />Variable time between injuries (Daily, Weekly, or Monthly)<br />
  15. 15. Methods<br />Gross examination of skull and brain<br />Edema assessment: wet-dry weight method<br />Immunohistochemistry: <br />Cell death<br />Axonal injury<br />BBB compromise<br />
  16. 16. Methods<br />Morris water maze hidden platform trials<br />5 trials, each consisting of 4 sub-trials, 1 per quadrant<br />Outcome = Latency to the platform<br />1 month or 1 year after final injury, <br /> platform location changed<br />
  17. 17. No Structural Injury<br /><ul><li>LOC 42”: 120.0 ± 20.8; </li></ul> 38”: 104.9 ±14.9; <br /> Sham: 45.3 ± 9.2s; p < 0.01 <br /><ul><li> No skull fractures
  18. 18. No intracranial hemorrhage
  19. 19. No contusion
  20. 20. No cerebral edema</li></ul> (77.5 ± 0.1 vs. 77.3 ± 0.4 %) <br />
  21. 21. CCI<br />Our model<br />Fluoro-Jade B<br />APP <br />(axon injury)<br />TUNEL <br />Anti-mouse IgG<br />Results: Histopathology<br />1 or 24h after 5th Injury: <br /><ul><li> Cortex
  22. 22. Hippocampus
  23. 23. Thalamus
  24. 24. Corpus callosum
  25. 25. Brain stem</li></li></ul><li>Morris Water Maze<br />OneConcussion<br />ThreeConcussions<br />Trial #<br />Trial #<br />(p=0.23, 6 mice per group)<br />(p=0.01, 8 mice per group)<br />TenConcussions<br />FiveConcussions<br />Trial #<br />Trial #<br />(p=0.01, 5 mice per group) <br />(p<0.01, 5 mice per group) <br />
  26. 26. Research Question 1<br />Are the cognitive effects of multiple concussions cumulative? <br />YES<br />
  27. 27. 5 Weekly Concussions<br />5 Daily Concussions<br />Trial #<br />Trial #<br />5 Monthly Concussions<br />Trial #<br />(p=0.66, 8 mice per group)<br />What is the optimal recovery time between concussions?<br />Trial #<br />(p=0.07, 7 mice per group)<br />(p=0.01, 5 mice per group)<br />
  28. 28. Research Question 2<br />Can the cognitive effects of multiple concussions be diminished by increasing the time interval between injuries? <br />YES<br />
  29. 29. 5 Daily Concussions<br />One Month Later<br />Trial #<br />Trial #<br />(p=0.01, 5 mice per group)<br />(p=0.01, 5 mice per group)<br />Do cognitive deficits after concussion resolve with time? One Month After Final Injury:<br />Trial #<br />
  30. 30. 5 Weekly Concussions<br />Trial #<br />One Month After Final Injury<br />One Month Later<br />Trial #<br />(p=0.07, 7 mice per group)<br />(p=0.02, 7 mice per group)<br />Do cognitive deficits after concussion resolve with time? One Month After Final Injury<br />* Suggests that the appropriate rest interval for sparing acute cognitive function may not be long enough to spare later cognitive effects. <br />
  31. 31. One Month Later<br />One Month Later<br />Trial #<br />Trial #<br />(p=0.21, 5 sham, 4 from 42”, 8 from 38”)<br />5 Monthly Concussions<br />Trial #<br />(p=0.66, 8 mice per group)<br />Do cognitive deficits after concussion resolve with time? One Month After Final Injury<br />Trial #<br />
  32. 32. One Year Later<br />5 Daily Concussions<br />One Year Later<br />One Year Later<br />Trial #<br />Trial #<br />Trial #<br />(p=0.01, 5 mice per group)<br />(p=0.02, 4 mice per group)<br />One Year Later<br />One Year After Final Injury<br />One Month Later<br />Trial #<br />Trial #<br />Trial #<br />
  33. 33. Conclusions<br />Repetitive, mild concussions produce cognitive deficits in the absence of significant structural injury. <br />The effects are cumulative<br />Acute cognitive outcomes improve as the interval between injuries is increased.<br />However, the rest interval required to reduce long-term effects may be longer than that required to diminish short-term effects. <br />
  34. 34. Future Studies<br />Currently repeating weekly <br />Further characterize model: silver staining, electron microscopy, long-term atrophy<br />Mechanism of cognitive dysfunction<br />
  35. 35. Acknowledgments<br />Michael J. Whalen, MD<br />Jimmy Zhang, Jugta Khuman, Chris Lee<br />NIH T32HD040128-06<br />National Football League Charities Foundation<br />
  36. 36.
  37. 37. Microgliosis<br />Our model<br />Sham<br />IBA 1 staining in cortex and hippocampus and periventricular areas<br />

×