BACKGROUND AND PURPOSE: There have been growing concerns around potential risks related to sports-related concussion and contact sport exposure to repetitive head impacts in young athletes. Here we investigate WM microstructural differences between collegiate football players with and without sports-related concussion. MATERIALS AND METHODS:The study included 78 collegiate athletes (24 football players with sports-related concussion, 26 football players with repetitive head impacts, and 28 non-contact-sport control athletes), available through the Federal Interagency Traumatic Brain Injury Research registry. Diffusion metrics of diffusion tensor/kurtosis imaging and WM tract integrity were calculated. Tract-Based Spatial Statistics and post hoc ROI analyses were performed to test group differences.RESULTS: Significantly increased axial kurtosis in those with sports-related concussion compared with controls was observed diffusely across the whole-brain WM, and some focal areas demonstrated significantly higher mean kurtosis and extra-axonal axial diffusivity in sports-related concussion. The extent of significantly different WM regions decreased across time points and remained present primarily in the corpus callosum. Similar differences in axial kurtosis were found between the repetitive head impact and control groups. Other significant differences were seen at unrestricted return-to-play with lower radial kurtosis and intra-axonal diffusivity in those with sports-related concussion compared with the controls, mainly restricted to the posterior callosum. CONCLUSIONS:This study highlights the fact that there are differences in diffusion microstructure measures that are present not only between football players with sports-related injuries and controls, but that there are also measurable differences between football players with repetitive head impacts and controls. This work reinforces previous work showing that the corpus callosum is specifically implicated in sports-related concussion and also suggests this to be true for repetitive head impacts. ABBREVIATIONS: AK ¼ axial kurtosis; AWF ¼ axonal water fraction; CC ¼ corpus callosum; D axon ¼ intra-axonal diffusivity; D e,|| ¼ extra-axonal axial diffusivity; D e,\ ¼ extra-axonal radial diffusivity; DKI ¼ diffusional kurtosis imaging; FA ¼ fractional anisotropy; HC ¼ healthy controls; MD ¼ mean diffusivity; MK ¼ mean kurtosis; RHI ¼ repetitive head impact; RK ¼ radial kurtosis; SCAT3 ¼ Sport Concussion Assessment Tool 3; SRC ¼ sports-related concussion; TBSS ¼ Tract-Based Spatial Statistics; WMTI ¼ white matter tract integrity

Purpose Repeated head impacts (RHI) without concussion may cause long-term sequelae. A growing array of diffusion MRI metrics exist, both empiric and modeled and it is hard to know which are potentially important biomarkers. Common conventional statistical methods fail to consider interactions between metrics and rely on group-level comparisons. This study uses a classification pipeline as a means towards identifying important diffusion metrics associated with subconcussive RHI. Methods 36 collegiate contact sport athletes and 45 non-contact sport controls from FITBIR CARE were included. Regional/whole brain WM statistics were computed from 7 diffusion metrics. Wrapper-based feature selection was applied to 5 classifiers representing a range of learning capacities. Best 2 classifiers were interpreted to identify the most RHI-related diffusion metrics. Results Mean diffusivity (MD) and mean kurtosis (MK) are found to be the most important metrics for discriminating between athletes with and without RHI exposure history. Regional features outperformed global statistics. Linear approaches outperformed non-linear approaches with good generalizability (test AUC 0.80–0.81). Conclusion Feature selection and classification identifies diffusion metrics that characterize subconcussive RHI. Linear classifiers yield the best performance and mean diffusion, tissue microstructure complexity, and radial extra-axonal compartment diffusion (MD, MK, De,⊥) are found to be the most influential metrics. This work provides proof of concept that applying such approach to small, multidimensional dataset can be successful given attention to optimizing learning capacity without overfitting and serves an example of methods that lead to better understanding of the myriad of diffusion metrics as they relate to injury and disease.