Assessing cerebral capillary function and stalling using single capillary reporters in ultrasound localization microscopy

While transcranial neuroimaging of individual capillary function holds transformative potential for diagnostics, it has proven difficult to achieve. Superresolution ultrasound, while capable of achieving micron-scale resolution, relies on the accumulation of multiple microbubble events, a method inherently limited by the exceedingly low probability of observing such events within capillaries. We present single capillary reporters (SCaRe), a paradigm-shifting approach that utilizes the complete flow trajectory information extracted from individual microbubbles to directly image single capillaries. This method allows for transcranial reconstruction and functional assessment of deep capillary networks in the entire brain. We employed computational simulations and pathological neuroinflammation models to quantify and validate metrics such as capillary transit-time and capillary stalling. Importantly, we demonstrated SCaRe's ability to resolve immune responses to injury at the single capillary level, markedly broadening research avenues for exploring microvascular dysfunction across diverse neurological conditions.