A preliminary model of football-related neural stress that integrates metabolomics with transcriptomics and virtual reality

Nicole L. Vike; Sumra Bari; Khrystyna Stetsiv; Alexa Walter; Sharlene Newman; Keisuke Kawata; Jeffrey J. Bazarian; Zoran Martinovich; Eric A. Nauman; Thomas M. Talavage; Linda Papa; Semyon M. Slobounov; Hans C. Breiter

doi:10.1016/j.isci.2021.103483

A preliminary model of football-related neural stress that integrates metabolomics with transcriptomics and virtual reality

Nicole L. Vike, Sumra Bari, Khrystyna Stetsiv, Alexa Walter, Sharlene Newman, Keisuke Kawata, Jeffrey J. Bazarian, Zoran Martinovich, Eric A. Nauman, Thomas M. Talavage, Linda Papa, Semyon M. Slobounov^*, Hans C. Breiter^*

^*Corresponding author for this work

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Research suggests contact sports affect neurological health. This study used permutation-based mediation statistics to integrate measures of metabolomics, neuroinflammatory miRNAs, and virtual reality (VR)-based motor control to investigate multi-scale relationships across a season of collegiate American football. Fourteen significant mediations (six pre-season, eight across-season) were observed where metabolites always mediated the statistical relationship between miRNAs and VR-based motor control (p_Sobel^perm ≤ 0.05; total effect > 50%), suggesting a hypothesis that metabolites sit in the statistical pathway between transcriptome and behavior. Three results further supported a model of chronic neuroinflammation, consistent with mitochondrial dysfunction: (1) Mediating metabolites were consistently medium-to-long chain fatty acids, (2) tricarboxylic acid cycle metabolites decreased across-season, and (3) accumulated head acceleration events statistically moderated pre-season metabolite levels to directionally model post-season metabolite levels. These preliminary findings implicate potential mitochondrial dysfunction and highlight probable peripheral blood biomarkers underlying repetitive head impacts in otherwise healthy collegiate football athletes.

Original language	English (US)
Article number	103483
Journal	iScience
Volume	25
Issue number	1
DOIs	https://doi.org/10.1016/j.isci.2021.103483
State	Published - Jan 21 2022

Funding

All work in this paper was funded by the listed academic institutions, and without specific NIH (United States), NSF (United States), or DoD (United States) support. Data collection was funded by SS's lab. MiRNA analysis was funded by LP's lab. Funding for metabolomic analysis, data integration, and manuscript preparation was funded by HB's lab (Warren Wright Adolescent Center). We thank the Pennsylvania State University football athletes for their participation in this study, along with Katie Finelli, Madeleine Scaramuzzo, and Peter H. Seidenberg, MD for their assistance with participant recruitment, clinical assessment, and data collection. We further thank John Csernansky, MD for his helpful comments and editing. Given the substantial guidance provided by the Reviewers of this work, we must note that all Reviewers met criteria to be considered authors of this work. Study concept/design: NLV, SB, HCB; Acquisition of original data: SS and AW; Coding of statistical tools: SB and NLV (with guidance from TMT, EAN, HCB); Analysis of data: NLV and SB (with guidance from HCB), LP (miRNA); Interpretation of data: NLV, SB, HCB (with input from KS, TMT, EAN, SN, KK, JJB, LP, SS); Statistical assessment: NLV and SB (with guidance from HCB); Authored original draft: NLV, SB, HCB; Generated figures: NLV; Revision of manuscript for content: NLV, SB, KS, AW, SN, KK, JJB, LP, EAN, TMT, SS, HCB; All authors approved the final version of the paper for submission. Dr. Papa is an inventor of a US patent application filed by Uniformed Services University of the Health Sciences (USUHS) regarding the potential utilities of selected miRNAs as diagnostic biomarkers for TBI. The other authors declare they have no financial or other conflicts of interest with regard to the data and analyses presented herein. The opinions expressed herein are those of the authors and are not necessarily representative of those from their respective institutions. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. All work in this paper was funded by the listed academic institutions, and without specific NIH (United States), NSF (United States), or DoD (United States) support. Data collection was funded by SS’s lab . MiRNA analysis was funded by LP’s lab . Funding for metabolomic analysis, data integration, and manuscript preparation was funded by HB’s lab (Warren Wright Adolescent Center). We thank the Pennsylvania State University football athletes for their participation in this study, along with Katie Finelli, Madeleine Scaramuzzo, and Peter H. Seidenberg, MD for their assistance with participant recruitment, clinical assessment, and data collection. We further thank John Csernansky, MD for his helpful comments and editing. Given the substantial guidance provided by the Reviewers of this work, we must note that all Reviewers met criteria to be considered authors of this work.

Keywords

Computer graphics
Metabolomics
Transcriptomics
Trauma

ASJC Scopus subject areas

General

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10.1016/j.isci.2021.103483

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Vike, N. L., Bari, S., Stetsiv, K., Walter, A., Newman, S., Kawata, K., Bazarian, J. J., Martinovich, Z., Nauman, E. A., Talavage, T. M., Papa, L., Slobounov, S. M., & Breiter, H. C. (2022). A preliminary model of football-related neural stress that integrates metabolomics with transcriptomics and virtual reality. iScience, 25(1), Article 103483. https://doi.org/10.1016/j.isci.2021.103483

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title = "A preliminary model of football-related neural stress that integrates metabolomics with transcriptomics and virtual reality",

abstract = "Research suggests contact sports affect neurological health. This study used permutation-based mediation statistics to integrate measures of metabolomics, neuroinflammatory miRNAs, and virtual reality (VR)-based motor control to investigate multi-scale relationships across a season of collegiate American football. Fourteen significant mediations (six pre-season, eight across-season) were observed where metabolites always mediated the statistical relationship between miRNAs and VR-based motor control (pSobelperm ≤ 0.05; total effect > 50%), suggesting a hypothesis that metabolites sit in the statistical pathway between transcriptome and behavior. Three results further supported a model of chronic neuroinflammation, consistent with mitochondrial dysfunction: (1) Mediating metabolites were consistently medium-to-long chain fatty acids, (2) tricarboxylic acid cycle metabolites decreased across-season, and (3) accumulated head acceleration events statistically moderated pre-season metabolite levels to directionally model post-season metabolite levels. These preliminary findings implicate potential mitochondrial dysfunction and highlight probable peripheral blood biomarkers underlying repetitive head impacts in otherwise healthy collegiate football athletes.",

keywords = "Computer graphics, Metabolomics, Transcriptomics, Trauma",

author = "Vike, {Nicole L.} and Sumra Bari and Khrystyna Stetsiv and Alexa Walter and Sharlene Newman and Keisuke Kawata and Bazarian, {Jeffrey J.} and Zoran Martinovich and Nauman, {Eric A.} and Talavage, {Thomas M.} and Linda Papa and Slobounov, {Semyon M.} and Breiter, {Hans C.}",

note = "Funding Information: All work in this paper was funded by the listed academic institutions, and without specific NIH (United States), NSF (United States), or DoD (United States) support. Data collection was funded by SS's lab. MiRNA analysis was funded by LP's lab. Funding for metabolomic analysis, data integration, and manuscript preparation was funded by HB's lab (Warren Wright Adolescent Center). We thank the Pennsylvania State University football athletes for their participation in this study, along with Katie Finelli, Madeleine Scaramuzzo, and Peter H. Seidenberg, MD for their assistance with participant recruitment, clinical assessment, and data collection. We further thank John Csernansky, MD for his helpful comments and editing. Given the substantial guidance provided by the Reviewers of this work, we must note that all Reviewers met criteria to be considered authors of this work. Study concept/design: NLV, SB, HCB; Acquisition of original data: SS and AW; Coding of statistical tools: SB and NLV (with guidance from TMT, EAN, HCB); Analysis of data: NLV and SB (with guidance from HCB), LP (miRNA); Interpretation of data: NLV, SB, HCB (with input from KS, TMT, EAN, SN, KK, JJB, LP, SS); Statistical assessment: NLV and SB (with guidance from HCB); Authored original draft: NLV, SB, HCB; Generated figures: NLV; Revision of manuscript for content: NLV, SB, KS, AW, SN, KK, JJB, LP, EAN, TMT, SS, HCB; All authors approved the final version of the paper for submission. Dr. Papa is an inventor of a US patent application filed by Uniformed Services University of the Health Sciences (USUHS) regarding the potential utilities of selected miRNAs as diagnostic biomarkers for TBI. The other authors declare they have no financial or other conflicts of interest with regard to the data and analyses presented herein. The opinions expressed herein are those of the authors and are not necessarily representative of those from their respective institutions. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Funding Information: All work in this paper was funded by the listed academic institutions, and without specific NIH (United States), NSF (United States), or DoD (United States) support. Data collection was funded by SS{\textquoteright}s lab . MiRNA analysis was funded by LP{\textquoteright}s lab . Funding for metabolomic analysis, data integration, and manuscript preparation was funded by HB{\textquoteright}s lab (Warren Wright Adolescent Center). We thank the Pennsylvania State University football athletes for their participation in this study, along with Katie Finelli, Madeleine Scaramuzzo, and Peter H. Seidenberg, MD for their assistance with participant recruitment, clinical assessment, and data collection. We further thank John Csernansky, MD for his helpful comments and editing. Given the substantial guidance provided by the Reviewers of this work, we must note that all Reviewers met criteria to be considered authors of this work. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = jan,

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doi = "10.1016/j.isci.2021.103483",

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AU - Bari, Sumra

AU - Stetsiv, Khrystyna

AU - Walter, Alexa

AU - Newman, Sharlene

AU - Kawata, Keisuke

AU - Bazarian, Jeffrey J.

AU - Martinovich, Zoran

AU - Nauman, Eric A.

AU - Talavage, Thomas M.

AU - Papa, Linda

AU - Slobounov, Semyon M.

AU - Breiter, Hans C.

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N2 - Research suggests contact sports affect neurological health. This study used permutation-based mediation statistics to integrate measures of metabolomics, neuroinflammatory miRNAs, and virtual reality (VR)-based motor control to investigate multi-scale relationships across a season of collegiate American football. Fourteen significant mediations (six pre-season, eight across-season) were observed where metabolites always mediated the statistical relationship between miRNAs and VR-based motor control (pSobelperm ≤ 0.05; total effect > 50%), suggesting a hypothesis that metabolites sit in the statistical pathway between transcriptome and behavior. Three results further supported a model of chronic neuroinflammation, consistent with mitochondrial dysfunction: (1) Mediating metabolites were consistently medium-to-long chain fatty acids, (2) tricarboxylic acid cycle metabolites decreased across-season, and (3) accumulated head acceleration events statistically moderated pre-season metabolite levels to directionally model post-season metabolite levels. These preliminary findings implicate potential mitochondrial dysfunction and highlight probable peripheral blood biomarkers underlying repetitive head impacts in otherwise healthy collegiate football athletes.

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A preliminary model of football-related neural stress that integrates metabolomics with transcriptomics and virtual reality

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