An Investigation of the Relationship Between Axonal Injury, Biomarker Expression and Mechanical Response in a Rodent Head Impact Acceleration Model

In the United States 1.4 million people sustain traumatic brain injury (TBI) each year, resulting in 235,000 hospitalizations and 50,000 fatalities annually. Traumatic axonal injury (TAI) is a serious outcome of TBI that accounts for 40-50% of hospitalizations due to head injury and one third of the mortality due to TBI, and it is difficult to diagnose and evaluate. The purpose of this dissertation is to determine mechanical injury predictors for TAI and identify potential biomarkers to evaluate TAI.

In this dissertation, a modified Marmarou impact acceleration injury model was developed to allow the monitoring of velocity of the impactor and characterization of head kinematics during impact. The rat head sustained linear acceleration and angular velocity of 918±281g and 116±45 rad/sec, respectively in 2.25m impacts, and 609±142g and 98±31 rad/sec, respectively in 1.25m impacts. The variability in head kinematics resulting from the same drop height suggested that monitoring of mechanical parameters are critical factors for illustration of the level of closed head injury with this model. Using this modified impact acceleration model, a series studies were performed to investigate correlation between impact mechanics and TAI, as well as correlation between biomarker levels and TAI.

In the first part of this dissertation, thirty-one anesthetized male Sprague-Dawley rats (392 ± 13 grams) were impacted using a modified impact acceleration injury device from 2.25 m and 1.25 m heights. Beta-amyloid precursor protein (β-APP) immunocytochemistry was used to assess and quantify axonal changes in CC and Py. Linear and angular responses of the rat head were monitored and measured in vivo with an attached accelerometer and angular rate sensor, and were correlated to TAI data. Logistic regression analysis suggested that the occurrence of severe TAI in CC was best predicted by average linear acceleration, followed by Power and time to surface righting. The combination of average linear acceleration and time to surface righting showed an improved predictive result. In Py, severe TAI was best predicted by time to surface righting, followed by peak and average angular velocity. When both CC and Py were combined, power was the best predictor, and the combined average linear acceleration and average angular velocity was also found to have good injury predictive ability.

In the second part of this dissertation, tweenty-four anesthetized male SpragueDawley rats were subjected to a closed head injury from 1.25, 1.75 and 2.25 m drop heights (n=8 for each group). 24 h after impact, cerebrospinal fluid (CSF) and serum were collected. CSF and serum levels of neurofilament H (NF-H), glial fibrillary acidic protein (GFAP), interleukin (IL)-6, and amyloid beta (Aβ) 1-42 were assessed by enzyme-linked immunosorbent assay (ELISA). Compared to controls, significantly higher CSF and serum pNF-H levels were observed in all impact groups, except between 1.25 m and control in serum. Furthermore, CSF and serum pNF-H levels were significantly different between the impact groups. For GFAP, both CSF and serum levels were significantly higher at 2.25 m compared to 1.75 m, 1.25 m and controls. There was no significant difference in CSF and serum GFAP levels between 1.75 m and 1.25 m, although both groups were significantly higher than control. TBI rats also showed significantly higher levels of IL-6 versus control in both CSF and serum, but no significant difference was observed between each impact group. Levels of Aβ were not significantly different between groups. Logistic regression analysis suggested that both pNF-H and GFAP levels in CSF and serum were good biomarkers for severe TBI. Pearson’s correlation analysis showed pNF-H and GFAP levels in CSF and serum had positive correlation with power (rate of impact energy), followed by average linear acceleration and surface righting (p<0.01), which were good predictors for traumatic axonal injury (TAI) according to histologic assessment in first part study, suggesting that they are directly related to the injury mechanism.

Year	Entry
1989	Gennarelli TA, Thibault LE, Tipperman R, Tomei G, Sergot R, Brown M, Maxwell WL, Graham DI, Adams JH, Irvine A, Gennarelli LM, Duhaime AC, Boock R, Greenberg J. Axonal injury in the optic nerve: a model simulating diffuse axonal injury in the brain. J Neurosurg. August 1989;71(2):244-253.
1997	Anderson RWG, Brown CJ, Scott G, Blumbergs PC, Finnie JW, McLean AJ, Jones NR. Biomechanics of a sheep model of axonal injury. In: Proceedings of the 1997 International IRCOBI Conference on the Biomechanics of Impact. September 24-26, 1997; Hannover, Germany.181-192.
2005	Viano DC, Casson IR, Pellman EJ, Bir CA, Zhang L, Sherman DC, Boitano MA. Concussion in professional football: comparison with boxing head impacts: part 10. Neurosurgery. December 2005;57(6):1154-1172.
1988	Lighthall JW. Controlled cortical impact: a new experimental brain injury model. J Neurotrauma. 1988;5(1):1-15.
1982	Adams JH, Graham DI, Murray LS, Scott G. Diffuse axonal injury due to nonmissile head injury in humans: an analysis of 45 cases. Ann Neurol. December 1982;12(6):557-563.
1981	Gennarelli TA, Adams JH, Graham DI. Acceleration induced head-injury in the monkey, I: the model, its biomechanical and physiological correlates. Acta Neuropathol Suppl. 1981;7:23-25.
2000	Smith DH, Meaney DF. Axonal damage in traumatic brain injury. Neuroscientist. December 2000;6(6):483-495.
2007	Kleiven S. Predictors for traumatic brain injuries evaluated through accident reconstructions. Stapp Car Crash J. 2007;51:81-114. SAE 2007-22-0003.
1994	Bandak FA, Eppinger RH. A three-dimensional finite element analysis of the human brain under combined rotational and translational accelerations. In: Proceedings of the 38th Stapp Car Crash Conference. October 31–November 2, 1994; Fort Lauderdale, FL. Warrendale, PA: Society of Automotive Engineers:145-163. SAE 942215.
1989	Pincemaille Y, Trosseille X, Mack P, Tarrière C, Breton F, Renault B. Some new data related to human tolerance obtained from volunteer boxers. In: Proceedings of the 33rd Stapp Car Crash Conference. October 4-6, 1989; Washington, DC. Warrendale, PA: Society of Automotive Engineers:177-190. SAE 892435.
1995	Smith DH, Soares HD, Pierce JS, Perlman KG, Saatman KE, Meaney DF, Dixon CE, McIntosh TK. A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. J Neurotrauma. April 1995;12(2):169-178.
2009	Shafieian M, Darvish KK, Stone JR. Changes to the viscoelastic properties of brain tissue after traumatic axonal injury. J Biomech. September 18, 2009;42(13):2136-2142.
2003	Anderson RWG, Brown CJ, Blumbergs PC, McLean AJ, Jones NR. Impact mechanics and axonal injury in a sheep model. J Neurotrauma. October 2003;20(10):961-974.
2003	Gennarelli TA, Pintar FA, Yoganandan N. Biomechanical tolerances for diffuse brain injury and a hypothesis for genotypic variability in response to trauma. In: 47th Annual Proceedings, Association for the Advancement of Automotive Medicine (AAAM). September 22-24, 2003; Lisbon, Portugal.624-628.
1995	McLean AJ. Brain injury without head impact? J Neurotrauma. August 1995;12(4):621-625.
1995	King AI, Ruan JS, Zhou C, Hardy WN, Khalil TB. Recent advances in biomechanics of brain injury research: a review. J Neurotrauma. August 1995;12(4):651-658.
2007	Fijalkowski RJ, Stemper BD, Pintar FA, Yoganandan N, Crowe MJ, Gennarelli TA. New rat model for diffuse brain injury using coronal plane angular acceleration. J Neurotrauma. August 2007;24(8):1387-1398.
1997	Smith DH, Chen X-H, Xu B-N, McIntosh TK, Gennarelli TA, Meaney DF. Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol & Exp Neurol. July 1997;56(7):822-834.
1995	Meaney DF, Smith DH, Shreiber DI, Bain AC, Miller RT, Ross DT, Gennarelli TA. Biomechanical analysis of experimental diffuse axonal injury. J Neurotrauma. November 1995;12(4):689-694.
1980	Ward C, Chan M, Nahum A. Intracranial pressure: a brain injury criterion. In: Proceedings of the 24th Stapp Car Crash Conference. October 15-17, 1980; Troy, MI. Warrendale, PA: Society of Automotive Engineers:163-185. SAE 801304.
1992	Povlishock JT. Traumatically induced axonal injury: pathogenesis and pathobiological implications. Brain Pathol. January 1992;2(1):1-12.
2003	King AI, Yang KH, Zhang L, Hardy W, Viano DC. Is head injury caused by linear or angular acceleration? In: Proceedings of the 2003 International IRCOBI Conference on the Biomechanics of Impact. September 25, 2003; Lisbon, Portugal.1-12.
1994	Marmarou A, Foda MAA-E, van den Brink W, Campbell J, Kita H, Demetriadou K. A new model of diffuse brain injury in rats, I: pathophysiology and biomechanics. J Neurosurg. February 1994;80(2):291-300.
2006	Singh A, Lu Y, Chen C, Kallakuri S, Cavanaugh JM. A new model of traumatic axonal injury to determine the effects of strain and displacement rates. Stapp Car Crash J. 2006;50:601-623. SAE 2006-22-0023.
1993	Galbraith JA, Thibault LE, Matteson DR. Mechanical and electrical responses of the squid giant axon to simple elongation. J Biomech Eng. February 1993;115(1):13-22.
1984	Prasad P, Mertz HJ. The position of the United States delegation to the ISO working group 6 on the use of HIC in the automotive environment. In: Proceedings of the SAE Government/industry Meeting & Exposition. May 20-23, 1984; Washington, DC. Warrendale, PA: Society of Automotive Engineers. SAE 851246.
1985	Margulies SS, Thibault LE, Gennarelli TA. A study of scaling and head injury criteria using physical model experiments. In: Proceedings of the 1985 International IRCOBI/AAAM Conference on the Biomechanics of Impact. September 24-26, 1985; Göteborg, Sweden.223-234.
2011	Centers for Disease Control and Prevention. Nonfatal traumatic brain injuries related to sports and recreation activities among persons aged ≤19 years: United States, 2001-2009. MMWR Morb Mortal Wkly Rep. October 7, 2011;60(39):1337-1342.
1968	Ommaya AK, Faas F, Yarnell P. Whiplash injury and brain damage: an experimental study. JAMA. April 22, 1968;204(4):285-289.
1998	Nishimoto T, Murakami S. Relation between diffuse axonal injury and internal head structures on blunt impact. J Biomech Eng. February 1998;120(1):140-147.
1982	Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol. 1982;12(6):564-574.
2004	Zhang L, Yang KH, King AI. A proposed injury threshold for mild traumatic brain injury. J Biomech Eng. 2004;126(2):226-236.
1989	McIntosh TK, Vink R, Noble L, Yamakami I, Fernyak S, Soares H, Faden AL. Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience. 1989;28(1):233-244.
2001	Zhang L, Yang KH, King AI. Biomechanics of neurotrauma. Neurol Res. March–April 2001;23(2-3):144-156.
2000	Newman JA, Shewchenko N, Welbourne E. A proposed new biomechanical head injury assessment function: the maximum power index. Stapp Car Crash J. 2000;44:215-247. SAE 2000-01-SC16.
1983	Povlishock JT, Becker DP, Cheng CLY, Vaughan GW. Axonal change in minor head injury. J Neuropathol & Exp Neurol. 1983;42(3):225-242.
2001	Bain AC, Raghupathi R, Meaney DF. Dynamic stretch correlates to both morphological abnormalities and electrophysiological impairment in a model of traumatic axonal injury. J Neurotrauma. May 2001;18(5):499-511.
1974	Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical scale. Lancet. July 13, 1974;2(7872):81-84.
2004	Stone JR, Okonkwo DO, Dialo AO, Rubin DG, Mutlu LK, Povlishock JT, Helm GA. Impaired axonal transport and altered axolemmal permeability occur in distinct populations of damaged axons following traumatic brain injury. Exp Neurol. November 2004;190(1):59-69.
2001	Gutierrez E, Huang Y, Haglid K, Bao F, Hansson H-A, Hamberger A, Viano D. A new model for diffuse brain injury by rotational acceleration, I: model, gross appearance, and astrocytosis. J Neurotrauma. March 2001;18(3):247-257.
1991	Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL. A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Meth. October 1991;39(3):253-262.
1956	Strich SJ. Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neutrosurg Psychiatry. August 1956;19(3):163-185.
1987	Dixon CE, Lyeth BG, Povlishock JT, Findling RL, Hamm RJ, Marmarou A, Young HF, Hayes RL. A fluid percussion model of experimental brain injury in the rat. J Neurosurg. July 1987;67(1):110-119.
2005	Duma SM, Manoogian SJ, Bussone WR, Brolinson PG, Goforth MW, Donnenwerth JJ, Greenwald RM, Chu JJ, Crisco JJ. Analysis of real-time head accelerations in collegiate football players. Clin J Sport Med. January 2005;15(1):3-8.
1993	Ruan JS, Khalil TB, King AI. Finite element modeling of direct head impact. In: Proceedings of the 37th Stapp Car Crash Conference. November 7-8, 1993; San Antonio, TX. Warrendale, PA: Society of Automotive Engineers:69-81. SAE 933114.
1993	Maxwell WL, Watt C, Graham DI, Gennarelli TA. Ultrastructural evidence of axonal shearing as a result of lateral acceleration of the head in non-human primates. Acta Neuropathol. July 1993;86(2):136-144.
2001	Zhang L, Yang KH, Dwarampudi R, Omori K, Li T, Chang K, Hardy WN, Khalil TB, King AI. Recent advances in brain injury research: a new human head model development and validation. Stapp Car Crash J. 2001;45:369-394. SAE 2001-22-0017.
2005	Newman JA, Beusenberg MC, Shewchenko N, Withnall C, Fournier E. Verification of biomechanical methods employed in a comprehensive study of mild traumatic brain injury and the effectiveness of American football helmets. J Biomech. July 2005;38(7):1469-1481.
1997	Maxwell WL, Graham DI. Loss of axonal microtubules and neurofilaments after stretch-injury to guinea pig optic nerve fibers. J Neurotrauma. September 1997;14(9):603-614.
1994	Ross DT, Meaney DF, Sabol MK, Smith DH, Gennarelli TA. Distribution of forebrain diffuse axonal injury following inertial closed head injury in miniature swine. Exp Neurol. April 1994;126(2):291-299.
2010	Faul M, Xu L, Wald MM, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; March 2010.
2011	Li Y, Zhang L, Kallakuri S, Zhou R, Cavanaugh JM. Injury predictors for traumatic axonal injury in a rodent head impact acceleration model. Stapp Car Crash J. 2011;55:25-47.
2005	Walilko TJ, Viano DC, Bir CA. Biomechanics of the head for Olympic boxer punches to the face. Br J Sports Med. October 2005;39(10):710-719.
2005	Franklyn M, Fildes B, Zhang L, Yang K, Sparke L. Analysis of finite element models for head injury investigation: reconstruction of four real-world impacts. Stapp Car Crash J. 2005;49:1-32. SAE 2005-22-0001.
2001	Zhang L, Yang KH, King AI. Comparison of brain responses between frontal and lateral impacts by finite element modeling. J Neurotrauma. 2001;18(1):21-30.
1994	Foda MAA-E, Marmarou A. A new model of diffuse brain injury in rats, II: morphological characterization. J Neurosurg. February 1994;80(2):301-313.
1966	Gadd CW. Use of a weighted-impulse criterion for estimating injury hazard. In: Proceedings of the 10th Stapp Car Crash Conference. November 8-9, 1966; Hollomon Air Force Base, NM. Warrendale, PA: Society of Automotive Engineers:164-174. SAE 660793.
1995	Povlishock JT, Christman CW. Traumatically induced axonal injury in animals and humans: a review of current thoughts. J Neurotrauma. June 1995;12(3):555-564.
2008	Deck C, Willinger R. Improved head injury criteria based on head FE model. Int J Crashworthiness. December 2008;13(6):667-678.
2012	Viano DC, Hamberger A, Bolouri H, Säljö A. Evaluation of three animal models for concussion and serious brain injury. Ann Biomed Eng. January 2012;40(1):213-226.
1960	Lissner HR, Lebow M, Evans FG. Experimental studies on the relation between acceleration and intracranial pressure changes in man. Surg Gynecol Obstet. September 1960;111(3):329-338.
1976	McElhaney JH, Roberts VL, Hilyard JF. Handbook of Human Tolerance. Tokyo, Japan: Japan Automobile Research Institute (JARI) Inc; 1976.
1971	Versace J. A review of the severity index. In: Proceedings of the 15th Stapp Car Crash Conference. November 17-19, 1971; Coronado, CA. Warrendale, PA: Society of Automotive Engineers:771-796. SAE 710881.
1992	Margulies SS, Thibault LE. A proposed tolerance criterion for diffuse axonal injury in man. J Biomech. August 1992;25(8):917-923.

Year

Entry

1989

Gennarelli TA, Thibault LE, Tipperman R, Tomei G, Sergot R, Brown M, Maxwell WL, Graham DI, Adams JH, Irvine A, Gennarelli LM, Duhaime AC, Boock R, Greenberg J. Axonal injury in the optic nerve: a model simulating diffuse axonal injury in the brain. J Neurosurg. August 1989;71(2):244-253.

1997

Anderson RWG, Brown CJ, Scott G, Blumbergs PC, Finnie JW, McLean AJ, Jones NR. Biomechanics of a sheep model of axonal injury. In: Proceedings of the 1997 International IRCOBI Conference on the Biomechanics of Impact. September 24-26, 1997; Hannover, Germany.181-192.

2005

Viano DC, Casson IR, Pellman EJ, Bir CA, Zhang L, Sherman DC, Boitano MA. Concussion in professional football: comparison with boxing head impacts: part 10. Neurosurgery. December 2005;57(6):1154-1172.

1988

Lighthall JW. Controlled cortical impact: a new experimental brain injury model. J Neurotrauma. 1988;5(1):1-15.

1982

Adams JH, Graham DI, Murray LS, Scott G. Diffuse axonal injury due to nonmissile head injury in humans: an analysis of 45 cases. Ann Neurol. December 1982;12(6):557-563.

1981

Gennarelli TA, Adams JH, Graham DI. Acceleration induced head-injury in the monkey, I: the model, its biomechanical and physiological correlates. Acta Neuropathol Suppl. 1981;7:23-25.

2000

Smith DH, Meaney DF. Axonal damage in traumatic brain injury. Neuroscientist. December 2000;6(6):483-495.

2007

Kleiven S. Predictors for traumatic brain injuries evaluated through accident reconstructions. Stapp Car Crash J. 2007;51:81-114. SAE 2007-22-0003.

1994

Bandak FA, Eppinger RH. A three-dimensional finite element analysis of the human brain under combined rotational and translational accelerations. In: Proceedings of the 38th Stapp Car Crash Conference. October 31–November 2, 1994; Fort Lauderdale, FL. Warrendale, PA: Society of Automotive Engineers:145-163. SAE 942215.

1989

Pincemaille Y, Trosseille X, Mack P, Tarrière C, Breton F, Renault B. Some new data related to human tolerance obtained from volunteer boxers. In: Proceedings of the 33rd Stapp Car Crash Conference. October 4-6, 1989; Washington, DC. Warrendale, PA: Society of Automotive Engineers:177-190. SAE 892435.

1995

Smith DH, Soares HD, Pierce JS, Perlman KG, Saatman KE, Meaney DF, Dixon CE, McIntosh TK. A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. J Neurotrauma. April 1995;12(2):169-178.

2009

Shafieian M, Darvish KK, Stone JR. Changes to the viscoelastic properties of brain tissue after traumatic axonal injury. J Biomech. September 18, 2009;42(13):2136-2142.

2003

Anderson RWG, Brown CJ, Blumbergs PC, McLean AJ, Jones NR. Impact mechanics and axonal injury in a sheep model. J Neurotrauma. October 2003;20(10):961-974.

2003

Gennarelli TA, Pintar FA, Yoganandan N. Biomechanical tolerances for diffuse brain injury and a hypothesis for genotypic variability in response to trauma. In: 47th Annual Proceedings, Association for the Advancement of Automotive Medicine (AAAM). September 22-24, 2003; Lisbon, Portugal.624-628.

1995

McLean AJ. Brain injury without head impact? J Neurotrauma. August 1995;12(4):621-625.

1995

King AI, Ruan JS, Zhou C, Hardy WN, Khalil TB. Recent advances in biomechanics of brain injury research: a review. J Neurotrauma. August 1995;12(4):651-658.

2007

Fijalkowski RJ, Stemper BD, Pintar FA, Yoganandan N, Crowe MJ, Gennarelli TA. New rat model for diffuse brain injury using coronal plane angular acceleration. J Neurotrauma. August 2007;24(8):1387-1398.

1997

Smith DH, Chen X-H, Xu B-N, McIntosh TK, Gennarelli TA, Meaney DF. Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol & Exp Neurol. July 1997;56(7):822-834.

1995

Meaney DF, Smith DH, Shreiber DI, Bain AC, Miller RT, Ross DT, Gennarelli TA. Biomechanical analysis of experimental diffuse axonal injury. J Neurotrauma. November 1995;12(4):689-694.

1980

Ward C, Chan M, Nahum A. Intracranial pressure: a brain injury criterion. In: Proceedings of the 24th Stapp Car Crash Conference. October 15-17, 1980; Troy, MI. Warrendale, PA: Society of Automotive Engineers:163-185. SAE 801304.

1992

Povlishock JT. Traumatically induced axonal injury: pathogenesis and pathobiological implications. Brain Pathol. January 1992;2(1):1-12.

2003

King AI, Yang KH, Zhang L, Hardy W, Viano DC. Is head injury caused by linear or angular acceleration? In: Proceedings of the 2003 International IRCOBI Conference on the Biomechanics of Impact. September 25, 2003; Lisbon, Portugal.1-12.

1994

Marmarou A, Foda MAA-E, van den Brink W, Campbell J, Kita H, Demetriadou K. A new model of diffuse brain injury in rats, I: pathophysiology and biomechanics. J Neurosurg. February 1994;80(2):291-300.

2006

Singh A, Lu Y, Chen C, Kallakuri S, Cavanaugh JM. A new model of traumatic axonal injury to determine the effects of strain and displacement rates. Stapp Car Crash J. 2006;50:601-623. SAE 2006-22-0023.

1993

Galbraith JA, Thibault LE, Matteson DR. Mechanical and electrical responses of the squid giant axon to simple elongation. J Biomech Eng. February 1993;115(1):13-22.

1984

Prasad P, Mertz HJ. The position of the United States delegation to the ISO working group 6 on the use of HIC in the automotive environment. In: Proceedings of the SAE Government/industry Meeting & Exposition. May 20-23, 1984; Washington, DC. Warrendale, PA: Society of Automotive Engineers. SAE 851246.

1985

Margulies SS, Thibault LE, Gennarelli TA. A study of scaling and head injury criteria using physical model experiments. In: Proceedings of the 1985 International IRCOBI/AAAM Conference on the Biomechanics of Impact. September 24-26, 1985; Göteborg, Sweden.223-234.

2011

Centers for Disease Control and Prevention. Nonfatal traumatic brain injuries related to sports and recreation activities among persons aged ≤19 years: United States, 2001-2009. MMWR Morb Mortal Wkly Rep. October 7, 2011;60(39):1337-1342.

1968

Ommaya AK, Faas F, Yarnell P. Whiplash injury and brain damage: an experimental study. JAMA. April 22, 1968;204(4):285-289.

1998

Nishimoto T, Murakami S. Relation between diffuse axonal injury and internal head structures on blunt impact. J Biomech Eng. February 1998;120(1):140-147.

1982

Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol. 1982;12(6):564-574.

2004

Zhang L, Yang KH, King AI. A proposed injury threshold for mild traumatic brain injury. J Biomech Eng. 2004;126(2):226-236.

1989

McIntosh TK, Vink R, Noble L, Yamakami I, Fernyak S, Soares H, Faden AL. Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience. 1989;28(1):233-244.

2001

Zhang L, Yang KH, King AI. Biomechanics of neurotrauma. Neurol Res. March–April 2001;23(2-3):144-156.

2000

Newman JA, Shewchenko N, Welbourne E. A proposed new biomechanical head injury assessment function: the maximum power index. Stapp Car Crash J. 2000;44:215-247. SAE 2000-01-SC16.

1983

Povlishock JT, Becker DP, Cheng CLY, Vaughan GW. Axonal change in minor head injury. J Neuropathol & Exp Neurol. 1983;42(3):225-242.

2001

Bain AC, Raghupathi R, Meaney DF. Dynamic stretch correlates to both morphological abnormalities and electrophysiological impairment in a model of traumatic axonal injury. J Neurotrauma. May 2001;18(5):499-511.

1974

Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical scale. Lancet. July 13, 1974;2(7872):81-84.

2004

Stone JR, Okonkwo DO, Dialo AO, Rubin DG, Mutlu LK, Povlishock JT, Helm GA. Impaired axonal transport and altered axolemmal permeability occur in distinct populations of damaged axons following traumatic brain injury. Exp Neurol. November 2004;190(1):59-69.

2001

Gutierrez E, Huang Y, Haglid K, Bao F, Hansson H-A, Hamberger A, Viano D. A new model for diffuse brain injury by rotational acceleration, I: model, gross appearance, and astrocytosis. J Neurotrauma. March 2001;18(3):247-257.

1991

Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL. A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Meth. October 1991;39(3):253-262.

1956

Strich SJ. Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neutrosurg Psychiatry. August 1956;19(3):163-185.

1987

Dixon CE, Lyeth BG, Povlishock JT, Findling RL, Hamm RJ, Marmarou A, Young HF, Hayes RL. A fluid percussion model of experimental brain injury in the rat. J Neurosurg. July 1987;67(1):110-119.

2005

Duma SM, Manoogian SJ, Bussone WR, Brolinson PG, Goforth MW, Donnenwerth JJ, Greenwald RM, Chu JJ, Crisco JJ. Analysis of real-time head accelerations in collegiate football players. Clin J Sport Med. January 2005;15(1):3-8.

1993

Ruan JS, Khalil TB, King AI. Finite element modeling of direct head impact. In: Proceedings of the 37th Stapp Car Crash Conference. November 7-8, 1993; San Antonio, TX. Warrendale, PA: Society of Automotive Engineers:69-81. SAE 933114.

1993

Maxwell WL, Watt C, Graham DI, Gennarelli TA. Ultrastructural evidence of axonal shearing as a result of lateral acceleration of the head in non-human primates. Acta Neuropathol. July 1993;86(2):136-144.

2001

Zhang L, Yang KH, Dwarampudi R, Omori K, Li T, Chang K, Hardy WN, Khalil TB, King AI. Recent advances in brain injury research: a new human head model development and validation. Stapp Car Crash J. 2001;45:369-394. SAE 2001-22-0017.

2005

Newman JA, Beusenberg MC, Shewchenko N, Withnall C, Fournier E. Verification of biomechanical methods employed in a comprehensive study of mild traumatic brain injury and the effectiveness of American football helmets. J Biomech. July 2005;38(7):1469-1481.

1997

Maxwell WL, Graham DI. Loss of axonal microtubules and neurofilaments after stretch-injury to guinea pig optic nerve fibers. J Neurotrauma. September 1997;14(9):603-614.

1994

Ross DT, Meaney DF, Sabol MK, Smith DH, Gennarelli TA. Distribution of forebrain diffuse axonal injury following inertial closed head injury in miniature swine. Exp Neurol. April 1994;126(2):291-299.

2010

Faul M, Xu L, Wald MM, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; March 2010.

2011

Li Y, Zhang L, Kallakuri S, Zhou R, Cavanaugh JM. Injury predictors for traumatic axonal injury in a rodent head impact acceleration model. Stapp Car Crash J. 2011;55:25-47.

2005

Walilko TJ, Viano DC, Bir CA. Biomechanics of the head for Olympic boxer punches to the face. Br J Sports Med. October 2005;39(10):710-719.

2005

Franklyn M, Fildes B, Zhang L, Yang K, Sparke L. Analysis of finite element models for head injury investigation: reconstruction of four real-world impacts. Stapp Car Crash J. 2005;49:1-32. SAE 2005-22-0001.

2001

Zhang L, Yang KH, King AI. Comparison of brain responses between frontal and lateral impacts by finite element modeling. J Neurotrauma. 2001;18(1):21-30.

1994

Foda MAA-E, Marmarou A. A new model of diffuse brain injury in rats, II: morphological characterization. J Neurosurg. February 1994;80(2):301-313.

1966

Gadd CW. Use of a weighted-impulse criterion for estimating injury hazard. In: Proceedings of the 10th Stapp Car Crash Conference. November 8-9, 1966; Hollomon Air Force Base, NM. Warrendale, PA: Society of Automotive Engineers:164-174. SAE 660793.

1995

Povlishock JT, Christman CW. Traumatically induced axonal injury in animals and humans: a review of current thoughts. J Neurotrauma. June 1995;12(3):555-564.

2008

Deck C, Willinger R. Improved head injury criteria based on head FE model. Int J Crashworthiness. December 2008;13(6):667-678.

2012

Viano DC, Hamberger A, Bolouri H, Säljö A. Evaluation of three animal models for concussion and serious brain injury. Ann Biomed Eng. January 2012;40(1):213-226.

1960

Lissner HR, Lebow M, Evans FG. Experimental studies on the relation between acceleration and intracranial pressure changes in man. Surg Gynecol Obstet. September 1960;111(3):329-338.

1976

McElhaney JH, Roberts VL, Hilyard JF. Handbook of Human Tolerance. Tokyo, Japan: Japan Automobile Research Institute (JARI) Inc; 1976.

1971

Versace J. A review of the severity index. In: Proceedings of the 15th Stapp Car Crash Conference. November 17-19, 1971; Coronado, CA. Warrendale, PA: Society of Automotive Engineers:771-796. SAE 710881.

1992

Margulies SS, Thibault LE. A proposed tolerance criterion for diffuse axonal injury in man. J Biomech. August 1992;25(8):917-923.

Year	Entry
2020	Zhou R. Development of Rat Head Finite Element Model and Tissue Level Biomechanical Threshold for Traumatic Axonal Injury [PhD thesis]. Detroit, MI: Wayne State University; May 2020.

Year

Entry

2020

Zhou R. Development of Rat Head Finite Element Model and Tissue Level Biomechanical Threshold for Traumatic Axonal Injury [PhD thesis]. Detroit, MI: Wayne State University; May 2020.