Embracing chaos: the scope and importance of clinical and pathological heterogeneity in mTBI

Mild traumatic brain injury (mTBI) manifests a wide array of clinical features, indicating great heterogeneity of its underlying pathologic features. mTBI diversity is related to pre-injury inter-individual differences and differences in the characteristics of each injury. This review summarizes key features of mTBI patients, their injuries and outcomes to give context to the scope of complexity inherent in this disorder. These differences are underscored by heterogeneity in postmortem pathology and in vivo imaging studies. Recognition, understanding and accounting for disease heterogeneity in mTBI are needed to enhance diagnosis and patient management, as approaches that do not account for inter-individual variation in pathology and patient characteristics relevant to real-life clinical trial participants, may entirely miss therapeutic targets. Refining our approach to TBI diagnosis, in light of inter-individual differences, can facilitate the development of effective prognostic tools and algorithms. New paradigms, which embrace heterogeneity of mTBI, in both preclinical and clinical investigation as well the appreciation of this variability in clinical care, offer much promise for enhancing outcomes and mitigating the burden of mTBI on its victims.