Abstracts

Rationale: Ictal neurodegeneration is thought to derive from excitotoxicity, which is unrelated to the vascular system and therefore should lead to spatially dissociated cell death with respect to the microvasculature. The state-of-the-art in hypoxia-based neural degeneration is that cells die in the watershed areas far from the vessels, because that is where oxygen perfusion is weakest. This is clear in stroke, in which arteriolar sources of blood flow are blocked or broken, leading to ischemia downstream. A fundamental assumption in the field, however, is that perfusion is controlled mechanically only by the arteriolar source, through the constriction and dilation of surface arteries and penetration arterioles that feed the underlying microvasculature. If so, it follows that oxygenation and metabolic function of neural tissue is entrained to arteriolar flow, with the final point of active flow control being the pre-capillary sphincter regulating flow from the arteriole to the primary capillary (Fig. 1a). In this classical view, arteriolar blockages, such as stroke, lead to pathological albeit uniform decreases in flow throughout the downstream capillary beds, leading to ischemia and neurodegeneration concentrated in neurons within the watershed areas farthest from irrigated vessels (Fig 1b). We tested the novel model that epilepsy affects blood flow at the capillary level in the hippocampus, which, if so, should lead to a previously undiscovered pattern of cell death in which neurodegeneration occurs near to vessels.Methods: Dual-Band Confocal Laser Endomicroscopy (CLE) of simultaneous pericyte activity and microscopic capillary blood flow is now beginning to test both of these theories directly, and determine their contributions to different diseases like stroke, but including diseases like epilepsy that were not previously categorized as blood flow diseases because microscopic blood flow could not be measured.Results: We have shown that abnormal capillary blood flow contributes to ictal neurodegeneration in epilepsy—creating non-uniform pericyte-capillary flow conditions that lead to neurodegeneration in neurons near ischemic microvessels (Fig 1c). We compared these results with recordings from the retina in a mouse model of Age-related Macular Degeneration (AMD), in which we discovered that abnormal arteriolar blood flow is abnormal and leads to neural degeneration far from microvessels as in Fig. 1b.Conclusions: These findings, together with new computational models of local metabolism as a function of uniform versus non-uniform microscopic blood flow, counterintuitively suggest that non-uniform capillary flow occurs during seizures, and can be especially dangerous when combined with the hyperemia found in epilepsy, accounting for 54% of ictal neurodegeneration.