1 Project Summary/Abstract 2 Anterior cruciate ligament (ACL) injury is a debilitating condition that results in consistent knee degeneration 3 and reduced physical activity capacity, with cumulative health care costs exceeding several billion dollars per 4 annum. The most common mechanism of ACL injury is without player to player contact (termed non-contact) 5 and secondary to motor coordination errors that result in injurious knee joint loading. As such, the current 6 standard for injury prevention is neuromuscular or movement training to correct resultant specific injury-risk 7 mechanics in controlled settings. However, injury reduction strategies have not achieved sufficient efficacy due 8 to inadequate targeting of central nervous system contributions to the motor errors that may underlie and 9 propagate injury-risk in ecologically valid settings. Our published prospective longitudinal data, and preliminary 10 ecologically valid sport-specific virtual reality data, indicates that sensorimotor brain activity underly ACL injury- 11 risk. Thus, the objective of this application is to determine the brain activity associated with injury-risk motor 12 control in standard and ecologically valid sport-specific virtual reality settings. Our preliminary data inform 13 our central hypothesis that those with injury-risk movement patterns rely on a visual and cognitive-motor neural 14 activation strategy, that is further accentuated in ecologically valid sport virtual reality. The proposed research is 15 innovative because it represents a new and substantial departure from prior work that focused primarily on 16 biomechanical outcomes, to now determine the neural activity propagating injury-risk knee motor control. A key 17 breakthrough of this proposal is the biomechanical instrumentation of knee motor control error in real-time during 18 neuroimaging. The expected outcomes from this observational trial will be the identification of the underlying 19 knee motor control neural activity related to ACL injury-risk biomechanics. Successful completion of the proposed 20 Aims will strategically position us to develop a competitive R01 clinical trial application that assesses novel 21 neuromuscular training to target the neural processes identified by this proposal. Specifically, guided by the 22 neural activation strategies identified herein, we will refine prevention programs using novel biofeedback 23 methods, clinical technologies, and motor learning principles to facilitate adaptive brain function that reduces 24 injury incidence. Thus, avoiding the lifelong pain, osteoarthritis, and physical activity limitations, directly aligning 25 with NIH initiatives to reduce injury and physical inactivity in youth and adults, which is the fourth leading cause 26 of global mortality. 27 28