Remote whole-brain functional microscopy of the vascular system: a paradigm shift for the monitoring and treatment of small vessel diseases

Project Information

MICROVASC

Grant agreement ID: 101070917

DOI

10.3030/101070917

EC signature date 11 July 2022

Start date 1 October 2022

End date 30 September 2027

Funded under

• The European Innovation Council (EIC)

Total cost

€ 3 946 172,50

EU contribution

€ 3 946 172,50

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 2 - MICROVASC (Remote whole-brain functional microscopy of the vascular system: a paradigm shift for the monitoring and treatment of small vessel diseases)

Reporting period: 2023-10-01 to 2025-01-31

Summary of the context and overall objectives of the project

Obtaining functional information on living organs non-invasively across different size scales is a tremendous challenge in medical imaging research, as diseases start locally at the cellular level deep into organs before expressing large-scale and observable symptoms. The unique complexity of the human brain adds another level of difficulty for neuroimaging. The cerebrovascular system consists of a multiscale network of blood vessels. Interaction between neurons and this vascular system, the so-called neurovascular coupling, is a major foundation of brain function leading to constant adaptation of the local cerebral blood flow to local metabolic demand. Its alteration is intimately linked to cerebral dysfunction. Current brain imaging modalities are essential for evaluating cerebrovascular diseases in patients but are restricted to millimetric resolution and fail to capture most of blood flow dynamics. Here, we propose to revolutionize the field of neuroimaging by introducing a groundbreaking technology called functional Ultrasound Localization Microscopy (fULM) capable of monitoring transcranially the whole human brain vasculature and function down to microscopic resolution. Beyond opening a complete paradigm shift in brain angiography (at least two orders of magnitude increase in spatial resolution), fULM will also be able to map the functional brain response during task-evoked and spontaneous activity at microscopic levels. We will address major technical challenges of ultrasound imaging, develop advanced neurocomputational analysis methods, validate our methods in preclinical models of cerebrovascular diseases and perform a First-In-Human study. Fundamental understanding of brain hemodynamics and neurovascular coupling as well as early clinical diagnosis of neurovascular abnormalities and evaluation of drug efficacy would tremendously benefit from such capabilities revealing both the brain vasculature and neurofunctional activity down to microscopic resolutions.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

MICROVASC project aims to develop a new technology, called functional ultrasound localization microscopy (fULM), capable of non-invasively image the whole human brain vasculature and function down to the micron scale. More specifically, the objectives of MICROVASC project are: (1) to build two unique fULM scanners (preclinical and clinical) and associated methodologies, (2) to demonstrate the potential of fULM in the context of inherited rare diseases with cerebrovascular manifestations.

In the second reporting period (from 01/10/2023 to 31/01/2025), we achieved the following objectives:
- To develop acquisition sequences for 3D ultrafast ultrasound imaging of the brain (WP1, deliverable D1.2 achieved)
- To develop processing methods for 3D super-localization (WP1, task 1.3 ongoing)
- To create new acquisition and processing strategies to maximize the spatial resolution of fULM (WP2, ongoing)
- To finalize the acquisition and visualization software for 3D preclinical fULM (WP3, D3.1 and D3.3 achieved)
- To finalize and obtain the authorizations for the preclinical protocols for fULM investigation in mouse models of cerebral small vessel diseases (WP4, D4.1 achieved)
- To build the hardware for a clinical fULM scanner (WP5, ongoing)
- To write the clinical protocols for investigating fULM in RVCL-S and HHT patients

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The main results of the second reporting period are:
– Preclinical fULM
. Transcranial 3D fULM in mice models has been developed and demonstrated, with validation of RCA probe technology. Seminal manuscript writing is currently ongoing for publication with Partner 1,2 and 4.
. Signal processing for 3D fULM imaging has been implemented, with further improvements to be made throughout the project.
– Functional connectivity analysis and signal processing
. A first pipeline for functional connectivity mapping using ULM has been implemented with Partner 1,2 and 4.
– Hardware and software development for fULM scanners
. The preclinical fULM scanner has been finalized, integrating hardware and software, and shipped to LUMC.
– Preclinical models and preclinical studies
. The endoglin knock-out (Eng-iKOe) mouse model has been studied and characterized. The seminal publication on the core concept of the project by Partner 1,2 and 3 has been accepted for publication in Nature Biomedical Engineering. A patent application has been filed.
. Effects of a therapeutic drug have been evaluated on this mouse model. The results confirms the ability of fULM to provide a precise monitoring of the effect of different drugs on the vascular phenotype of the disease. This was also a major preclinical outcome of the project.
– Clinical translation
. The hardware for the clinical fULM scanner has been built
. A headset has been specifically design to hold the ultrasound probe for transcranial fULM acquisitions in humans
. The full regulatory documentation have been prepared and are ready for application to authorization for human use. Clinical protocol is currently under discussion for a submission to the IRB of LUMC (Partner 4).