Functional ultrasound microscopy: probing the activity of the whole brain at the microscopic level

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Functional ultrasound localization microscopy of the rat brain (Photo: Alexandre

Functional ultrasound localization microscopy of the rat brain (Photo: Alexandre Dizeux / Physics for Medicine Paris)

Ultrasound is transforming the field of neuroimaging, thanks to technological advances made over the last decade by the Physics for Medicine laboratory (Inserm, ESPCI Paris - PSL, CNRS). The introduction of functional ultrasound imaging (fUS) in 2009 provided neuroscientists with a unique technology - portable, easy to use, and reasonably priced - to visualize brain activity with high sensitivity. In 2015, another method, called ultrasound localization microscopy (ULM), produced novel images of the cerebral vascular network, revealing blood vessels just a few micrometers in diameter.

Now, in 2022, research teams in the Physics for Medicine lab are achieving even more dramatic results by combining the advantages of both methods: functional ultrasound localization microscopy (fULM) captures brain activity across the entire brain at the microscopic scale. The study has just been published in the journal Nature Methods . It opens up major future prospects in the clinic for the diagnosis of cerebrovascular pathologies, such as strokes, all small vessel diseases, and other diseases.It opens up major future clinical perspectives for the diagnosis of cerebrovascular pathologies, such as strokes, all diseases of small vessels, risks of aneurysm rupture or vascular alterations present very early in neurodegenerative diseases such as Alzheimer’s disease.

Ultrasound scanners - imaging systems based on the use of ultrasound waves - allow organs to be observed through the skin, and their use is therefore widespread in diagnostic imaging and medical monitoring, particularly in obstetrics and cardiology. However, the use of ultrasound for neuroimaging remains limited to the detection of large cerebral blood vessels (several millimeters in diameter). However, looking at smaller details of the cerebral vascular network represents a major challenge in medicine, as many neurodegenerative diseases (Alzheimer’s disease, dementia, etc.) are now known to be linked to the presence of large blood vessels.) are now known to be linked to dysfunctions of the small cerebral blood vessels.

Neurovascular coupling: a dialogue between the vascular and neuronal networks
neuronal networks

Vascular and neuronal activities are closely linked in the brain: blood vessels supply neurons with oxygen and nutrients, and are thus essential for neuronal activity. This fundamental interaction, called neurovascular coupling, is exploited for neuroimaging: the detection of variations in blood flow provides information on neuronal activation.

Functional ultrasound imaging (fUS) does this with very high sensitivity, i.e. it can detect very subtle changes in cerebral blood volume.

It also brings the other advantages inherent in ultrasound, namely the ability to image large fields of view covering the entire brain and to discern details of a few hundred microns.

To detect smaller blood vessels, researchers in the Physics for Medicine laboratory have developed a technique called ultrasound localization microscopy (ULM), which achieves much better spatial resolution than conventional ultrasound.

Imagine a view of the sky over Paris, on which you are trying to discern a very narrow road. This may be a difficult task. However, if a bicycle equipped with a lamp is riding on this road, you will see its halo and the center of the halo will indicate the position of the bicycle very precisely, revealing the position of the narrow road.

Localization microscopy is based on the same principle: the position of a bright point object can be localized very precisely by locating the center of its halo. In the case of the ULM method, the "shining" objects are bio-compatible gas bubbles of a few microns in diameter, injected into the bloodstream.

By tracking these microscopic bubbles as they travel through the bloodstream, blood vessels can be located with microscopic resolution across the wide fields of view of ultrasound imaging.

By accumulating the trajectories of millions of microbubbles, scientists have reconstructed unique images of the anatomy of the whole-brain microvasculature of first rodents, and then patients, as demonstrated in previous studies (Demené et al., Science Translational Medicine 2017; Demeulenaere et al., eBioMedicine 2022). However, the ULM technique is not fast enough or sensitive enough to capture dynamic blood flow variations related to neuronal activity.

Probing brain activity at the microscopic level non-invasively

In the current study, published in Nature Methods , the research team overcame this hurdle and took the analysis of microbubble trajectories within a rat’s cerebral vascular network much further. They not only imaged the brain microvasculature, but also detected neuronal activation by calculating the number and speed of microbubbles passing through each blood vessel: when a brain region becomes active, blood volume increases locally due to neurovascular coupling, dilating blood vessels and opening the passageway for more bubbles. In other words, it becomes possible to extract dynamic information from ULM data.

Tracking microbubbles is not only used to localize microvessels, but also to probe functional activity at the microvessel level.

All these technological developments give rise to a new imaging modality in its own right: functional ultrasound localization microscopy (fULM), a unique combination of three major advantages (non-invasive quantification of brain activityactivity, at microscopic resolution, and across the entire brain, all integrated in an easy-to-use and relatively low-cost ultrasound scanner).

The fULM proof of concept marks a decisive advance in neuroimaging, but it is only a first step towards a vast field of applications in neuroscience.

Each of the millions of microbubbles imaged during a fULM acquisition carries quantities of physiological and biological information that remain to be explored. Scientists will now work on exploiting, processing and dissecting these huge quantities of data to link them to the mechanisms involved in cerebrovascular and neurodegenerative diseases.


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