A transparent miniscope-integrated ultrasound platform enables concurrent focused neuromodulation and wide-field imaging in freely moving mice
This paper introduces SonoMod, an open-source, transparent miniscope-integrated platform that enables concurrent focused ultrasound neuromodulation and wide-field calcium imaging in freely moving mice by utilizing a novel optically transparent transducer and lens system.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
To understand the brain, scientists often need to do two things at once: they must gently poke a specific part of the neural circuit to see how it reacts, and they must watch the entire network light up in response. For decades, these two tasks have been difficult to combine in a living, moving animal. The tools used to stimulate the brain, such as focused ultrasound, have traditionally been bulky and opaque, blocking the view needed for cameras to see the brain's activity. Conversely, the tiny cameras used to watch neurons fire usually require the animal to be still and its head held in place, preventing the study of natural behavior. This creates a gap in knowledge, leaving researchers unable to see how the brain's complex circuits change in real time when an animal is free to move, explore, and interact with its world.
A team of researchers has now bridged this gap by creating a device that allows them to stimulate and watch the brain simultaneously in a mouse that is walking freely. They built a lightweight, transparent headset that combines a miniature camera with a special ultrasound generator. This device, which they named SonoMod, sits on the mouse's head like a tiny backpack. It uses sound waves to gently stimulate specific areas of the brain while a camera looks through the same transparent window to record the resulting activity across the entire surface of the brain. The breakthrough lies in making the sound-generating part of the device see-through, allowing light to pass through it just as easily as sound, so the camera never loses its view.
The core of this invention is a transparent ultrasound transducer, a disk that generates sound waves but is made of a clear crystal material rather than the usual opaque metal or ceramic. To focus these sound waves onto a precise spot deep inside the brain, the researchers attached a custom-made lens to the front of the disk. This lens is so thin and clear that it does not blur the image for the camera. The researchers used advanced 3D printing to shape the lens with microscopic precision, creating a pattern on its surface that bends the sound waves into a tight beam without distorting the light passing through it. They also filled the gap between the lens and the mouse's skull with a special oil that matches the way both light and sound travel through the materials, ensuring that neither the image nor the sound gets scattered or lost.
The entire assembly is designed to be modular and interchangeable. The researchers created different versions of the lens that can be quickly swapped out, allowing them to target different regions of the brain without needing to build a new device for each experiment. One version of the lens focuses the sound on the secondary motor cortex, an area involved in planning movement, while another version targets the retrosplenial cortex, which is important for memory and navigation. The device is small enough that it adds only about 3.2 grams to the mouse, a weight the animal can easily carry without altering its natural behavior. It connects to a standard open-source camera system that is widely used in neuroscience, making the technology accessible to other labs without requiring specialized, expensive equipment.
In their tests, the researchers placed the device on mice that were awake and moving freely. They first confirmed that the camera could see clearly through the transparent lens, capturing detailed images of blood vessels and brain activity across a wide area, covering nearly the entire top surface of the brain. They then used the device to deliver focused bursts of ultrasound to specific targets. When they stimulated the motor cortex, the camera immediately recorded a surge of activity in that specific area, while other parts of the brain remained calm. This proved that the sound was hitting only the intended target and not accidentally stimulating the whole brain.
The study also revealed how the brain communicates across its two halves. When the researchers stimulated the motor cortex on one side, the camera detected a signal that traveled to the matching area on the opposite side of the brain a fraction of a second later. This kind of wide-field view is something that older, single-point recording methods could not capture, as they only look at one tiny spot at a time. The researchers also checked that the device was safe for the animals, measuring the temperature rise caused by the sound waves and finding it to be negligible, far below the level that could harm brain tissue.
By combining focused stimulation with a wide-angle view of the brain in a freely moving animal, this new platform offers a powerful way to study how neural circuits work in real life. It allows scientists to ask questions about how specific brain regions influence behavior and how signals travel between different parts of the brain, all while the animal is doing what it does best: moving and exploring. The researchers made the designs for the device available to the public, hoping that this open approach will help others build on their work to further unravel the mysteries of the brain.
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