Stalled Capillary Blood Flow in the Brain: New Measurement Tools Unveil a Critical Role in Neurological Diseases

Flow disturbances in the smallest blood vessels of the brain, the capillaries, have long been considered a potential cause of brain dysfunction. However, owing to the technological challenge of studying blood flow in three-dimensional capillary networks, elucidating the incidence, causes, and consequences of capillary obstructions has been difficult. Advances in optical microscopes for in vivo imaging, primarily high-spatiotemporal-resolution optical coherence tomography and two-photon microscopy, have recently enabled detailed studies of these capillary stalling events in both healthy and diseased mice. In this review, we describe these imaging approaches to quantify capillary stalling, identifying strengths and weaknesses of different methods. We then review recent findings on the incidence, molecular and cellular causes, and physiological and neurological consequences of capillary stalling across multiple mouse models of brain disease, including Alzheimer's disease, stroke, and traumatic brain injury. We conclude by suggesting necessary next steps in instrumentation and analysis for studying capillary stalling, as well as how to address key unanswered questions about underlying mechanisms for capillary stalling in the brain and how this phenomenon may impact disease progression and cognitive function.