Altering the Trajectory of Perfusion-Diffusion Deficits Using A BDNF Mimetic Acutely After TBI is Associated with Improved Functional Connectivity

Traumatic brain injury (TBI) results in metabolic deficits and functionally compromised tissue. The BDNF mimetic R13 has a significant positive effect on both tissue metabolism and behavioral outcome after TBI, indicating a promising therapeutic. To understand the mechanism of action for this intervention, we determined whether there was any association between the underlying metabolic insult and any improvement in resting state functional connectivity (FC) with MRI, or whether R13 acts through mechanisms unrelated to metabolic recovery. We found perfusion deficits could be reasonably approximated by reductions in mean diffusivity (MD) acutely after injury, because a majority of regions with low perfusion matched to regions of low MD, indicative of cell swelling. Injury alone resulted in reduced cross-brain FC and contralateral hyperconnectivity at 1d compared to sham and these were spatially coincident with regions of low MD. R13 intervention at 1–7d altered the tissue trajectory of MD pathology away from pseudo-normalization so that a greater volume of tissue remained with low MD at 7d. These same regions were associated with significant changes in cross-brain and contralateral FC in R13 treated rats compared to injured vehicle-treated rats. These data indicate a likely metabolic effect of R13 acutely after injury.