Periodic Reporting for period 5 - ResolveStroke (Stroke diagnostic imaging performed with ultrafast ultrasound localization microscopy (uULM))
Reporting period: 2024-09-01 to 2025-02-28
The ERC ResolveStroke project attempts to create a new imaging technique that can map all the blood vessels within the adult human brain (brain angiography). It exploits an innovative approach called ultrasound localization microscopy (ULM), which tracks micrometric contrast agents traveling among red blood cells. As it relies on ultrasound, we can envision such a technique to be implemented in a small portable imaging scanner, which could have a major impact on the treatment of strokes.
Strokes represent one of the main causes of death across the world. It is also the primary cause of handicaps. This disease can be caused by a blockage of a blood vessel within the brain (ischemic stroke) or a rupture of a blood vessel (hemorrhagic stroke). Stroke needs to be treated within a few hours to lessen its impact. Unfortunately, treatment can only be provided after diagnostic is performed imaging - with MRI and CT currently - to distinguish ischemic and hemorrhagic stroke. Unfortunately, access to these imaging tools is limited worldwide and, due to this situation, the great majority of stroke patients remain untreated.
The project ResolveStroke aims to transform ULM into an emergency diagnostic tool that can be brought to the patient rapidly, removing the current hurdle preventing rapid treatment. Its objectives are 1) convert current 2D ULM into a full 3D ultrasound angiography 2) image through the animal model and human skull 3) Provide an angiography at the micrometric scale 4) Define what distinguishes ischemic and hemorrhagic stroke on ULM images 5) Demonstrate its use in models and humans.
Strokes represent one of the main causes of death across the world. It is also the primary cause of handicaps. This disease can be caused by a blockage of a blood vessel within the brain (ischemic stroke) or a rupture of a blood vessel (hemorrhagic stroke). Stroke needs to be treated within a few hours to lessen its impact. Unfortunately, treatment can only be provided after diagnostic is performed imaging - with MRI and CT currently - to distinguish ischemic and hemorrhagic stroke. Unfortunately, access to these imaging tools is limited worldwide and, due to this situation, the great majority of stroke patients remain untreated.
The project ResolveStroke aims to transform ULM into an emergency diagnostic tool that can be brought to the patient rapidly, removing the current hurdle preventing rapid treatment. Its objectives are 1) convert current 2D ULM into a full 3D ultrasound angiography 2) image through the animal model and human skull 3) Provide an angiography at the micrometric scale 4) Define what distinguishes ischemic and hemorrhagic stroke on ULM images 5) Demonstrate its use in models and humans.
The ERC Consolidator Grant ResolveStroke built upon our foundational work in Ultrasound Localization Microscopy (ULM), which initially demonstrated 2D super-resolution imaging of the rat brain using microbubble tracking with micrometric spatial and microsecond temporal resolution. The overarching goal of the ERC Consolidator project ResolveStroke was to advance ULM into a portable 3D scanner capable of rapid stroke diagnosis, specifically to distinguish between ischemic and hemorrhagic strokes and enable faster triage and thrombolytic treatment.
Through this project, we transformed ULM from a 2D technique, originally limited to healthy rats without a skull, into a 3D clinical imaging modality suitable for transcranial and abdominal applications.
We generalized ULM to 3D, enabling precise quantification of microbubble movement and amplitude, which allowed for detailed mapping of microvascular flow and structure. To address the computational bottleneck, we developed algorithms that reduced ULM processing times from 12 hours to just 3 minutes in 2D, a critical step toward real-time clinical feasibility. Additionally, we systematically identified the physical factors limiting ULM resolution, optimizing imaging parameters for both preclinical and clinical settings.
Preclinical studies were expanded to include 3D ULM imaging in animal models, where we developed biomarkers to differentiate between ischemic and hemorrhagic stroke types. A major technical achievement was the successful demonstration of 3D ULM through a sheep skull, which validated the feasibility of transcranial imaging in large animals and paved the way for human applications.
Clinical translation was a central focus of ResolveStroke. We performed 2D ULM imaging in moyamoya patients and completed 3D ULM clinical imaging in 19 ischemic stroke patients. A dedicated human stroke scanner was developed and deployed in a clinical study, with regulatory approval from ANSM.
To ensure reproducibility and foster collaboration, we distributed all 2D ULM codes, along with datasets and comparative metrics, to the global research community. To support broader adoption, we also published and distributed 3D ULM codes alongside a study demonstrating 3D ULM in awake mice.
The project also led to the launch of the ResolveStroke startup in 2022, co-founded with Vincent Hingot and Aritz Zamacola, which now employs 15 people and focuses on commercializing 3D transcranial contrast-enhanced ultrasound for cerebrovascular disease diagnosis. Further clinical applications were explored through two ERC Proof-of-Concept grants: StrokeMonitor (2022), which implemented ULM for detecting delayed cerebral ischemia in intensive care units, with a study completed on 13 patients and KidneyScope (2024), which will extend 3D ULM to glomerular imaging in chronic kidney disease and kidney transplants.
Additionally, we applied 2D ULM in neonates with strokes and arteriovenous malformations, in a collaboration with the team of F. Knieling in Erlangen.
Beyond neuroimaging, ResolveStroke expanded ULM’s applications to renal imaging, where we achieved the first visualization of glomeruli in human kidneys using clinical ultrasound scanners. This breakthrough allowed for the non-invasive assessment of glomerular density and microvascular architecture, offering a potential diagnostic tool for chronic kidney disease and kidney transplant monitoring.
Collectively, these advancements established ULM as a robust, clinically translatable imaging modality, setting the stage for its broader application in neurovascular and abdominal imaging.
Through this project, we transformed ULM from a 2D technique, originally limited to healthy rats without a skull, into a 3D clinical imaging modality suitable for transcranial and abdominal applications.
We generalized ULM to 3D, enabling precise quantification of microbubble movement and amplitude, which allowed for detailed mapping of microvascular flow and structure. To address the computational bottleneck, we developed algorithms that reduced ULM processing times from 12 hours to just 3 minutes in 2D, a critical step toward real-time clinical feasibility. Additionally, we systematically identified the physical factors limiting ULM resolution, optimizing imaging parameters for both preclinical and clinical settings.
Preclinical studies were expanded to include 3D ULM imaging in animal models, where we developed biomarkers to differentiate between ischemic and hemorrhagic stroke types. A major technical achievement was the successful demonstration of 3D ULM through a sheep skull, which validated the feasibility of transcranial imaging in large animals and paved the way for human applications.
Clinical translation was a central focus of ResolveStroke. We performed 2D ULM imaging in moyamoya patients and completed 3D ULM clinical imaging in 19 ischemic stroke patients. A dedicated human stroke scanner was developed and deployed in a clinical study, with regulatory approval from ANSM.
To ensure reproducibility and foster collaboration, we distributed all 2D ULM codes, along with datasets and comparative metrics, to the global research community. To support broader adoption, we also published and distributed 3D ULM codes alongside a study demonstrating 3D ULM in awake mice.
The project also led to the launch of the ResolveStroke startup in 2022, co-founded with Vincent Hingot and Aritz Zamacola, which now employs 15 people and focuses on commercializing 3D transcranial contrast-enhanced ultrasound for cerebrovascular disease diagnosis. Further clinical applications were explored through two ERC Proof-of-Concept grants: StrokeMonitor (2022), which implemented ULM for detecting delayed cerebral ischemia in intensive care units, with a study completed on 13 patients and KidneyScope (2024), which will extend 3D ULM to glomerular imaging in chronic kidney disease and kidney transplants.
Additionally, we applied 2D ULM in neonates with strokes and arteriovenous malformations, in a collaboration with the team of F. Knieling in Erlangen.
Beyond neuroimaging, ResolveStroke expanded ULM’s applications to renal imaging, where we achieved the first visualization of glomeruli in human kidneys using clinical ultrasound scanners. This breakthrough allowed for the non-invasive assessment of glomerular density and microvascular architecture, offering a potential diagnostic tool for chronic kidney disease and kidney transplant monitoring.
Collectively, these advancements established ULM as a robust, clinically translatable imaging modality, setting the stage for its broader application in neurovascular and abdominal imaging.
The ERC Consolidator Grant ResolveStroke achieved transformative progress in Ultrasound Localization Microscopy (ULM), advancing it far beyond its initial state as a 2D preclinical technique. At the project’s outset, ULM was confined to laboratory settings, with limited spatial resolution, lengthy processing times, and no clinical applicability. By the project’s conclusion, we had redefined ULM as a 3D clinical imaging modality, capable of high-resolution visualization of microvascular networks in both animal models and human patients. These advancements collectively positioned ULM as a portable, non-invasive imaging modality, poised for integration into routine clinical practice for cerebrovascular and abdominal diseases. The project’s outcomes not only advanced the state of the art in medical imaging but also established a foundation for future innovations in microvascular diagnostics.