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

iScience. 2021 Dec 15;25(1):103483. doi: 10.1016/j.isci.2021.103483. eCollection 2022 Jan 21.

Authors

Nicole L Vike¹, Sumra Bari¹, Khrystyna Stetsiv¹, Alexa Walter², Sharlene Newman³, Keisuke Kawata^{4

5}, Jeffrey J Bazarian⁶, Zoran Martinovich¹, Eric A Nauman^{7

8

9}, Thomas M Talavage^{7

10

11}, Linda Papa¹², Semyon M Slobounov², Hans C Breiter^{1

13}

Affiliations

¹ Warren Wright Adolescent Center Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
² Department of Kinesiology, Pennsylvania State University, University Park, PA 16801, USA.
³ Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA.
⁴ Department of Kinesiology, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA.
⁵ Program in Neuroscience, College of Arts and Sciences, Indiana University, Bloomington, IN 47405, USA.
⁶ Department of Emergency Medicine, University of Rochester, Rochester, NY 14627, USA.
⁷ Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
⁸ School of Mechanical Engineering, Purdue University, West Lafayette, IN 47907, USA.
⁹ Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA.
¹⁰ School of Electrical and Computer Engineering, Purdue University, West Lafayette, IN 47907, USA.
¹¹ Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45221, USA.
¹² Department of Emergency Medicine, Orlando Regional Medical Center, Orlando, FL 32806, USA.
¹³ Laboratory of Neuroimaging and Genetics, Department of Psychiatry, Massachusetts General Hospital and Harvard School of Medicine, Boston, MA 02114, USA.

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 ( $p_{S o b e l}^{p e r m}$ $\leq$ 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.

Grants and funding

R01 NS057676/NS/NINDS NIH HHS/United States