Behavioral- and bio-markers of subconcussion with controlled human head impact

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The long-term goals of this project are to determine how repeated, subclinical brain stress may lead to clinically significant brain damage, and to use this knowledge to prevent cumulative neurological disability. Sub-concussion is an under-recognized phenomenon, in which cranial impact does not lead to clinical symptoms, but when repeated frequently, can cause measurable neurological dysfunction in athletes and others engaged in activities that introduce mild mechanical stresses to the brain. Little is known about how brain tissue injury develops and resolves at the cellular level in these cases because no individual episode of physical trauma is sufficiently strong enough to cause outwardly observable concussion symptoms. Such sub-concussive blows occur frequently during the course of normal play (blocking in football, heading in soccer, etc.). However, without obvious clinical signs, underlying neurological damage goes unnoticed, players return to play and damage can accumulate over time. The proposed project is based on the premise that mild mechanical impact introduces brain stress unobservable by self-examination, or common diagnostics, but detectable by specialized behavioral tests and cutting-edge extracelluar vesicle analysis techniques. Such techniques could determine when it is safe or dangerous to resume the activity. Using soccer heading to induce mild mechanical stress on brain tissue, we have established an innovative human experimental paradigm that is indicative of commonly experienced stress levels during sports/recreational activities. With this paradigm, we will develop new tools to characterize the neurological effects of sub-concussive impact. In Aim 1, we will quantify behavioral effects of mild head impact using sensitive measures of postural stability during standing and walking. In Aim 2, we will determine a circulating molecular pattern of subconcussive head injury using an innovative technique for blood brain barrier- and CNS cell-derived microvesicle profiling. In Aim 3, we will identify a unique microRNA signature of subconcussive head impact in circulating exosomes using cutting-edge sequencing technology. The proposed study is innovative because it will introduce an entirely new dimension to the pathophysiology of subconcussive head impact. Results of this project will potentially lead to the development of innovative behavioral and molecular diagnostic tools to assess risk of cumulative brain injury.