Multi-scale Mapping of Cellular Alterations in Brain Tissue due to Concussion

At the cellular level, traumatic brain injury (TBI) initiates a complex web of pathological alterations in all the types of brain cells, ranging from individual cells to multi-cellular functional units at multiple scales ranging from niches to the layered brain cytoarchitecture. Unfortunately, current immunohistochemistry (IHC) methods reveal only a fraction of these alterations at a time, miss the many other alterations and side effects that are occurring concurrently, and do not provide quantitative readouts. The potential consequence of unobserved and untreated cellular alterations is high, as they may contribute to confounding, co-morbid, or persistent conditions (e.g., depression, headaches, stress-related health problems). Importantly, the current state of drug development for brain pathologies leaves much to be desired, with a recent review concluding that “most of the pharmacologic and non-pharmacologic treatments have failed to demonstrate significant efficacy on both the clinical symptoms as well as the pathophysiologic cascade responsible for the permanent brain injury”. In this talk, I will describe a practical approach to pathological brain tissue mapping with a focus on combination drug treatment. Our approach is based on replacing the many low information content assays with a single comprehensive assay based on imaging and analyzing highly multiplexed whole brain sections using 10 – 50 molecular markers, sufficient to analyze all the major brain cell types and their functional states over extended regions.