ObjectiveStudies of outcome after traumatic brain injury (TBI) are hampered by the lack of robust injury severity measures that can accommodate spatial-anatomical and mechanistic heterogeneity. In this study we introduce a Mahalanobis distance measure (M) as an intrinsic injury severity measure that combines in a single score the many ways a given injured brain's connectivity can vary from that of healthy controls. Our objective is to test the hypotheses that M is superior to univariate measures in (1) discriminating patients and controls and (2) correlating with cognitive assessment.MethodsSixty-five participants (34 with mild TBI, 31 controls) underwent diffusion tensor MRI and extensive neuropsychological testing. Structural connectivity was inferred for all participants for 22 major white matter connections. Twenty-two univariate measures (1 per connection) and 1 multivariate measure (M), capturing and summarizing all connectivity change in a single score, were computed.ResultsOur multivariate measure (M) was able to better discriminate between patients and controls (area under the curve 0.81) than any individual univariate measure. M significantly correlated with cognitive outcome (Spearman ρ = 0.31; p < 0.05). No univariate measure showed significant correlation after correction for multiple comparisons.ConclusionsHeterogeneity in the severity and distribution of injuries after TBI has traditionally complicated the understanding of outcomes after TBI. Our approach provides a single, continuous variable that can fully capture individual heterogeneity. M's ability to distinguish even mildly injured patients from controls and its correlation with cognitive assessment suggest utility as an imaging-based marker of intrinsic injury severity.