Functional ultrasound localization microscopy (fULM): a revolutionary technique for detecting and diagnosing diseases of the brain’s smallest blood vessels

Teams from Physics for Medicine and LUMC are developing a revolutionary technique to non-invasively visualize changes in the brain’s smallest blood vessels using functional ultrasound microscopy (fULM).

A study recently published in Nature Biomedical Engineering demonstrates that, for the first time, it is possible to noninvasively detect cerebrovascular alterations linked to pericyte dysfunction in the brains of mice. As part of the EIC Pathfinder Microvasc project, this study was conducted by Nicolas Zucker (Ph.D. student at the Physics for Medicine Paris Institute, ESPCI engineering graduate, class of 137) in collaboration with Jérémy Thalgott (Ph.D. student, Leiden University Medical Center) and supervised by researchers Mickael Tanter (ESPCI Paris, France) and Franck Lebrin (Inserm, Leiden University Medical Center, Netherlands).

Pericytes are contractile cells located on the walls of capillaries that help regulate blood flow. These cells play a key role in the early stages of many cerebrovascular diseases and are therefore a promising target for the development of new treatments. However, the mechanisms linking pericyte dysfunction to changes in cerebral vasculature remain only partially understood, and to date, there is no noninvasive method for reliably identifying them in the human brain.

In our study, we show that it is possible to observe these early changes in cerebral microvessels in mice using a noninvasive imaging technique developed at the Institute of Physics for Medicine in 2022 (See article), called functional ultrasound microscopy (fULM). Using a model of a rare genetic vascular disease (hereditary hemorrhagic telangiectasia, which affects one in 5,000 people worldwide and is associated with severe bleeding), in which a specific gene is inactivated in blood vessel cells, detachment of pericytes is observed in an area connecting arterioles and capillaries.

The results of ultrasound localization imaging show that the capillaries have irregular shapes, increased diameters, reduced blood flow velocity in the arterioles, and impaired neurovascular coupling. These non-invasive observations represent promising biomarkers for monitoring pericyte dysfunction throughout the entire brain.

Finally, ultrasound imaging reveals that treating mice with the compound (C381), which activates the TGF-β signaling pathway, restores both the structure of the cerebral arteries and their hemodynamic responses.

Our study shows that, for the first time, it is possible to image vascular and neurovascular alterations in small cerebral vessels, as well as the recovery of their functions during various therapeutic treatments, in a completely noninvasive manner. With the development of super-resolved ultrasound imaging in humans, this work paves the way for a better understanding of the effect of pericyte alterations on cerebral circulation and for studying the effect of treatments targeting pericytes in patients.