Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?

Sandy R. Shultz, Lisa Cardamone, Ying R. Liu, R. Edward Hogan, Luigi MacCotta, David K. Wright, Ping Zheng, Amelia Koe, Marie Claude Gregoire, John P. Williams, Rodney J. Hicks, Nigel C. Jones, Damian E. Myers, Terence J. O'Brien, Viviane Bouilleret

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE. Methods Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video- electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52% (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings. Key Findings MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, 18F- fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month 18F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination. Significance These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group.

Original languageEnglish
Pages (from-to)1240-1250
Number of pages11
JournalEpilepsia
Volume54
Issue number7
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

Keywords

  • Epileptogenesis
  • Lateral fluid percussion injury
  • MRI
  • PET
  • Posttraumatic epilepsy

Cite this

Shultz, Sandy R. ; Cardamone, Lisa ; Liu, Ying R. ; Edward Hogan, R. ; MacCotta, Luigi ; Wright, David K. ; Zheng, Ping ; Koe, Amelia ; Gregoire, Marie Claude ; Williams, John P. ; Hicks, Rodney J. ; Jones, Nigel C. ; Myers, Damian E. ; O'Brien, Terence J. ; Bouilleret, Viviane. / Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?. In: Epilepsia. 2013 ; Vol. 54, No. 7. pp. 1240-1250.
@article{72a216f382fd4dd597e22b17d532a6c2,
title = "Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?",
abstract = "Purpose Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE. Methods Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video- electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52{\%} (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings. Key Findings MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, 18F- fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month 18F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination. Significance These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group.",
keywords = "Epileptogenesis, Lateral fluid percussion injury, MRI, PET, Posttraumatic epilepsy",
author = "Shultz, {Sandy R.} and Lisa Cardamone and Liu, {Ying R.} and {Edward Hogan}, R. and Luigi MacCotta and Wright, {David K.} and Ping Zheng and Amelia Koe and Gregoire, {Marie Claude} and Williams, {John P.} and Hicks, {Rodney J.} and Jones, {Nigel C.} and Myers, {Damian E.} and O'Brien, {Terence J.} and Viviane Bouilleret",
year = "2013",
month = "7",
doi = "10.1111/epi.12223",
language = "English",
volume = "54",
pages = "1240--1250",
journal = "Epilepsia",
issn = "0013-9580",
publisher = "John Wiley & Sons",
number = "7",

}

Shultz, SR, Cardamone, L, Liu, YR, Edward Hogan, R, MacCotta, L, Wright, DK, Zheng, P, Koe, A, Gregoire, MC, Williams, JP, Hicks, RJ, Jones, NC, Myers, DE, O'Brien, TJ & Bouilleret, V 2013, 'Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?' Epilepsia, vol. 54, no. 7, pp. 1240-1250. https://doi.org/10.1111/epi.12223

Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome? / Shultz, Sandy R.; Cardamone, Lisa; Liu, Ying R.; Edward Hogan, R.; MacCotta, Luigi; Wright, David K.; Zheng, Ping; Koe, Amelia; Gregoire, Marie Claude; Williams, John P.; Hicks, Rodney J.; Jones, Nigel C.; Myers, Damian E.; O'Brien, Terence J.; Bouilleret, Viviane.

In: Epilepsia, Vol. 54, No. 7, 07.2013, p. 1240-1250.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?

AU - Shultz, Sandy R.

AU - Cardamone, Lisa

AU - Liu, Ying R.

AU - Edward Hogan, R.

AU - MacCotta, Luigi

AU - Wright, David K.

AU - Zheng, Ping

AU - Koe, Amelia

AU - Gregoire, Marie Claude

AU - Williams, John P.

AU - Hicks, Rodney J.

AU - Jones, Nigel C.

AU - Myers, Damian E.

AU - O'Brien, Terence J.

AU - Bouilleret, Viviane

PY - 2013/7

Y1 - 2013/7

N2 - Purpose Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE. Methods Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video- electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52% (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings. Key Findings MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, 18F- fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month 18F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination. Significance These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group.

AB - Purpose Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE. Methods Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video- electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52% (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings. Key Findings MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, 18F- fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month 18F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination. Significance These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group.

KW - Epileptogenesis

KW - Lateral fluid percussion injury

KW - MRI

KW - PET

KW - Posttraumatic epilepsy

UR - http://www.scopus.com/inward/record.url?scp=84879798916&partnerID=8YFLogxK

U2 - 10.1111/epi.12223

DO - 10.1111/epi.12223

M3 - Article

VL - 54

SP - 1240

EP - 1250

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 7

ER -