Assessing cerebral capillary function and stalling using single capillary reporters in ultrasound localization microscopy, 2026, Lee et al.

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

Spoiler: Authors

Lee, Stephen A; Leconte, Alexis; Wu, Alice; Kinugasa, Joshua; Palacios, Gerardo Ramos; Porée, Jonathan; Sadikot, Abbas F; Linninger, Andreas; Provost, Jean

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 SCaRes ability to resolve immune responses to injury at the single capillary level, markedly broadening research avenues for exploring microvascular dysfunction across diverse neurological conditions.

SIGNIFICANCE
Growing evidence indicates that the brains microvascular system plays a key role in neurological diseases and aging. This is especially true for capillaries, the smallest blood vessels, that interact directly with neurons. However, imaging and measuring the function of these tiny vessels through the skull remains extremely challenging. Here, we introduce single capillary reporters (SCaRe), statistically derived biomarkers that track the movement of individual microbubbles to directly image and assess single capillaries in ultrasound localization microscopy. SCaRe surpasses the spatial and temporal limitations of current techniques, enabling the extraction of markers that reflect capillary function in both healthy and diseased brains. These biomarkers reveal immune-related responses to brain injury with single capillary precision.

Web | DOI | PDF | Proceedings of the National Academy of Sciences | Open Access

 

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Commentary in Capillary transit time heterogeneity comes into focus (2026, PNAS, Paywall)

While cerebral blood flow and blood volume have long dominated discussions of brain perfusion, theoretical and experimental work over the past two decades has converged on a subtler but more fundamental determinant of tissue oxygenation: The distribution of transit times through the capillary network. Even when bulk flow is preserved, excessive capillary transit time heterogeneity (CTH) can markedly reduce oxygen extraction efficiency by allowing a fraction of blood to traverse the microvascular bed too rapidly for adequate exchange, a phenomenon predicted to produce paradoxical flow–metabolism uncoupling under pathological conditions. In this framework, capillary dysfunction emerges as an important constraint on neuronal metabolism, linking microvascular health directly to cognitive function, aging, and vulnerability to injury.

Despite its central role in neurovascular physiology, CTH has proven remarkably difficult to measure directly in vivo. […] many hypotheses connecting altered CTH to aging, dementia, stroke, and neuroinflammation have remained constrained by technology rather than by ideas. This disconnect between theory and measurement has been especially acute for phenomena that are intrinsically heterogeneous and rare, such as prolonged capillary dwell times or transient stalling events, which may disproportionately impair oxygen delivery while remaining invisible to spatially averaged or depth-limited imaging approaches. In this issue, Lee et al. introduce a trajectory-based ultrasound localization microscopy framework that enables direct measurement of capillary transit times across the brain.

By enabling capillary identification and transit time estimation from individual trajectories, this approach makes it possible to measure capillary transit time heterogeneity at brain-wide scale. Importantly, the output is not a single summary metric but a spatially resolved distribution of transit times, preserving the heterogeneity that theory predicts to be physiologically consequential. Capillary dwell times can be mapped across cortical depth and into subcortical structures (such as the hippocampus and white matter), revealing regional differences that have long been hypothesized but rarely observed directly.

By making capillary transit time heterogeneity experimentally accessible at whole-brain scale, this work lowers a long-standing barrier between theory and measurement in neurovascular physiology. Questions that have remained largely conceptual-such as how capillary dysfunction emerges with aging, how it evolves during neurodegeneration, or how it responds to injury and inflammation-can now be addressed directly and longitudinally in vivo. The method is already well suited for repeated measurements over time and for integration with behavioral, physiological, or functional readouts.

More broadly, this study reframes capillaries from being statistically elusive structures to being individually interpretable functional units. Capillary transit time heterogeneity, long treated as an inferred or model-dependent quantity, becomes a measurable variable grounded in the dynamics of single blood-borne tracers. By shifting attention from averaged flow to the trajectories that generate it, this work transforms a central concept in microvascular physiology into an experimentally testable property of the living brain. In doing so, it provides a powerful new lens through which to study the vascular foundations of brain health and disease.