Neurophotonic Advances for Mechanistic Investigation of the Role of Capillary Dysfunction in Stroke Recovery

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ABSTRACT Neuroimaging methods are invaluable for managing the treatment of stroke patients in the acute phase of guiding reperfusion and salvaging tissue, and are being used more and more to understand the effect of and ultimately guide treatments in the chronic phase of functional brain recovery. At least some degree of functional recovery is widely observed in most patients in the months following stroke. The exact biological mechanism directing this recovery is under active investigation. BOLD functional Magnetic Resonance Imaging (fMRI) and functional Near Infrared Spectroscopy (fNIRS), both of which non-invasively measure the vascular response to brain activity, are valuable tools for longitudinal monitoring of stroke patients during this recovery period. However, these vascular responses to external stimuli in brain regions damaged by ischemic stroke are almost always altered relative to that in brain regions contra-lateral to the stroke and to that seen in healthy individuals. It is not known if this alteration is a reflection of underlying differences in the neuronal function or simply a result of damaged vasculature altering the vascular response to activity. In other words, we do not know the effect of stroke on neurovascular coupling and are thus limited in our ability to use these valuable neuroimaging tools to study functional recovery in stroke survivors. It is known that stroke triggers a prominent vascular reorganization and neurovascular unit changes in the periinfarct cortex. It is not known whether the efficiency of this vascular reorganization contributes to the neurophysiological recovery of the periinfarct cortex, and whether it is linked to the final functional outcome. Further, it is not known whether periinfarct neurovascular unit changes and capillary flow quality are a simple reflection of underlying neural recovery or can be a primary determinant of subsequent neural reorganization. Therefore, there is a great need for studies in well-established and properly controlled preclinical stroke models to evaluate the evolution of the structural and functional aspects of chronic neurovascular recovery, for a better mechanistic understanding of these biological interactions, and to understand their prognostic value for predicting behavioral outcomes following stroke. Our aims are designed to meet these needs by using a novel combination of optical technologies and a preclinical stroke model. We first establish the utility of the novel technology for longitudinal imaging of stroke. We will then utilize these approaches to find the association of hemodynamic recovery signatures with capillary flow stalls. Finally, we investigate mechanistic explanations for the heterogeneity of these changes.