The midbrain is biomechanically susceptible to force loading from repetitive subconcussive head impacts (RSHI), is a site of tauopathy in chronic traumatic encephalopathy (CTE), and regulates functions (e.g., eye movements) often disrupted in concussion. In a prospective longitudinal design, we demonstrate there are reductions in midbrain white matter integrity due to a single season of collegiate football, and that the amount of reduction in midbrain white matter integrity is related to the amount of rotational acceleration to which players’ brains are exposed. We then replicate the observation of reduced midbrain white matter integrity in a retrospective cohort of individuals with frank concussion, and further show that variance in white matter integrity is correlated with levels of serum-based tau, a marker of blood-brain barrier disruption. These findings mean that noninvasive structural MRI of the midbrain is a succinct index of both clinically silent white matter injury as well as frank concussion.
Bibliographical noteFunding Information:
We thank J. Gill for assistance with the tau analyses, C.-J. Lin for assistance and direction using LibSVM, T. Durant and H. Angulo for development of software to support visualization of the spatial distribution of head impacts (Figs. 1 and 6), and B. Feely for development of the interactive web platform reproducing those findings (www. openbrainproject.org). We thank E. Vanoost for helping with the computational architecture that made this work possible. We also thank the Riddell Corporation for providing the information necessary to interpret azimuth and elevation data from the helmet-worn accelerometers. Funding: This study was supported by funds from the NFL Charities (www.nflcharities-org.ezpminer.urmc.rochester.edu/) and NIH K24 HD064754 to J.J.B., National Institute of Nursing Research Intramural Research Program, U.S. Army Rapid Innovation Fund (W911NF- 11-R-0017) to D.W.W., NIH grant R01 MH099921 to G.S., and NIH grants R21NS076176, R01NS089609, and R01EY028535 to B.Z.M. A.A.H. is a trainee in the Medical Scientist Training Program funded by NIH T32 GM007356. Further support for A.A.H. was provided by University of Rochester UL1 TR002001 via the NIH/National Center for Advancing Translational Sciences, BWF-IIMP Pilot Project, and a predoctoral training grant to the Clinical & Translational Sciences Institute (TL1 TR002000). F.E.G. was supported by a University of Rochester Center for Visual Science predoctoral training fellowship (NIH training grant 5T32EY007125-24) and a Moss Rehabilitation Research Institute postdoctoral training fellowship (NIH T32HD007425). S.H. was supported, in part, by NIH grant R01MH118257. D.P. was supported by a grant from the University of Rochester Clinical and Translational Science Institute (CTSI TL1 TR000096). The opinions in this manuscript do not constitute endorsement by the Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of Defense, or the U.S. Government of the information contained therein. More generally, no funders had a role in the study design, data collection, data analysis, decision to publish, or preparation of the