Highly sensitive, non-invasive functional connectivity mapping in the mouse brain using simultaneous multi-slice fUS imaging

Just published in the journal Imaging Neuroscience is a new paper that describes the performance of our IcoPrime-4D MultiArray probe for uncovering resting-state networks in the brains of awake, active mice. Unlike previous approaches, our ‘simultaneous multi-slice’ scanning technology is both highly sensitive and non-invasive, opening up new possibilities for understanding brain function.

Being able to determine 3D resting-state networks of the mouse brain using functional ultrasound (fUS), quickly and non-invasively, has the potential to revolutionize neuroscience research. Indeed, it’s something we’ve been working towards ever since we got started in fUS over 10 years ago.

The challenge stems from the need to receive ultrasound responses from the entire brain over a sufficiently short timeframe. Sequential scanning of multiple 2D slices using a motorized linear stage is one option, but the tradeoff between the field of view and scanning time makes it impossible to obtain high-quality functional connectivity data. Using 2D matrix or row–column arrays is another possibility, but the reduced sensitivity of this approach means that invasive craniotomy is required, to avoid signal loss caused when ultrasound echoes pass through the skull.

Of course, determining 3D resting-state networks is possible using fMRI, but this comes with several difficulties, most notably the need to average signals over multiple acquisitions in order to improve the inherently low signal-to-noise ratios – a process that makes uncovering correlations much more difficult.

 

IcoPrime 4D Multi Array: Simultaneous multi-slice technology

The release of our IcoPrime-4D MultiArray probe addresses the above-mentioned limitations by using a scanning system, developed by staff at Iconeus and Physics for Medicine Paris, that in essence combines both approaches.

Firstly, the probe contains four high-sensitivity linear transducer arrays that simultaneously acquire four sets of 2D slices. Next, moving the probe laterally across the brain in a stepwise fashion, and repeating the scanning

operation three times, enables coverage of the whole mouse brain in a total of 16 slices, without the need for a craniotomy.

Importantly, the whole process using this ‘simultaneous multi-slice’ technology is complete within less than 3 seconds, enabling correlations between fluctuations of spontaneous blood flow to be detected, and resting-state functional connectivity maps to be compiled – in three dimensions.

High-sensitivity, transcranial, brain-wide scanning

The simultaneous multi-slice scanning technology, and the results of using it for the non-invasive study of mice, are now described in a new paper published in the journal Imaging Neuroscience.

An important aspect mentioned in the paper is the improvement in sensitivity that is achievable using the new approach, with higher peak amplitudes resulting in the ability to image smaller blood vessels than either of the previously-mentioned fUS approaches.

The paper then moves on to discuss the validation of the new methodology, first by assessing its ability to visualize brain activation in anesthetized mice following light stimulation. This was a straightforward ‘benchmark’ experiment in which the equipment (as expected) performed very well.

More crucially, the paper then discusses the probe’s performance for resting-state functional connectivity mapping in awake, normally-behaving mice. The authors determined the resting-state activity of 200 segmented regions, and were able to identify large-scale functional connections spanning several coronal slices. The results are best summarized by the authors, who say: “Together, these observations attest to the high sensitivity of our approach through its ability to detect reliable spontaneous coactivations in the deepest regions of the mouse brain, even in the transcranial setting”.

Exciting research opportunities

Ludovic Lecointre, Pharm.D., CEO and co-founder of Iconeus, emphasizes the potential of the IcoPrime-4D MultiArray probe: “As clearly demonstrated in this paper, the new probe outperforms other options for 3D fUS imaging in the mouse, in terms of its sensitivity, non-invasiveness, speed and resolution. Not only that, but it also circumvents the difficulties that have long hampered the use of fMRI for functional connectivity studies”.

“I believe it’s this ability to understand in more detail the functional connections between the parts of the mouse brain where the new probe will prove most valuable. The most exciting applications lie in helping us to understand how the brain operates – for example, in neuropsychiatric diseases, where functional organization is often disrupted”.

“Congratulations to the team at Iconeus and Physics for Medicine Paris on this groundbreaking study – it marks a new chapter in the study of the mouse brain, and I look forward enthusiastically to the new insights that will stem from it!”.

 

Are you interested in integrating fUS using IcoPrime-4D MultiArray into your lab? Please contact us and we’ll arrange a call to discuss your needs.

 

Reference:

A. Bertolo, J. Ferrier, S. Cazzanelli, S. Diebolt, M. Tanter, S. Pezet, M. Pernot, B.F. Osmanski and T. Deffieux, High sensitivity mapping of brain-wide functional networks in awake mice using simultaneous multi-slice fUS imaging, Imaging Neuroscience, 2023 (accepted), https://doi.org/10.1162/imag_a_00030T.

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