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St. Louis Washington University Team Releases Latest Research Findings

St. Louis, June 28, 2024—Brain diseases like Parkinson's disease involve damage across multiple brain regions, necessitating new neural modulation technologies that can precisely and flexibly regulate all affected areas simultaneously. Recently, Professor Chen Hong's team at Washington University in St. Louis published a paper in the Proceedings of the National Academy of Sciences of the United States of America, introducing their creation of "AhSonogenetics," an Airy beam holographic sonogenetics technology. This non-invasive technique combines holographic acoustic devices with genetic engineering to precisely target affected neurons in the brain, adjusting specific cells in multiple diseased brain regions for therapeutic purposes. Researchers have achieved significant results in experiments targeting Parkinson's disease in mice.

Wearable ultrasound device design (A–C) using Airy-beam holographic metasurfaces and characterization of manufactured device (D–F). (A) A schematic representation outlining the critical steps involved in Airy-beam metasurface design. The process begins with the initial design by calculating the Airy-beam function amplitude profile, which was converted to binary phase values. This was then followed by optimizing Airy function parameters, including r0 and ω, which are scaled by the wavelength λ, to meet the specific requirements for the intended brain target location and the desired focal region size. The optimized design was then evaluated by numerical simulations of transcranial ultrasound field propagation. (B) The designed metasurface is fabricated through 3D printing and calibrated using a hydrophone in a water tank with an ex vivo mouse skull placed in front of the metasurface. (C) The wearable ultrasound device is manufactured by integrating the metasurface with a circular-shaped lead zirconate titanate (PZT) ceramic element. A housing was 3D-printed and plugged into a baseplate glued to the mouse head. Three examples are presented to showcase the device’s capability in (D) off-center beam steering, (E) dynamic beam steering along the wave-propagation direction by adjusting the ultrasound frequency without altering the metasurface, and (F) dual focusing. In each case, the Top panel displays the 3D design of the metasurface, the Middle panel presents the numerical simulations of the generated ultrasound fields with the metasurface on the top and yellow highlights denoting the mouse skull, and the Bottom panel shows the experimental measurements of the generated ultrasound fields with the white outlines corresponding to brain anatomy in reference to the Allen brain atlas.

Credit:https://doi.org/10.1073/pnas.2402200121.

Manipulating Ultrasound Beams to Focus on Diseased Areas

In 2021, Chen Hong's team introduced the concept of sonogenetics, employing viral vectors carrying ultrasound-sensitive ion channels selectively delivered to neurons in the brain. By using low-intensity focused ultrasound (FUS) to deliver minimal heat, they activated these channels, thereby stimulating neurons. Chen Hong explained, "We identified ion channels in neurons that respond to ultrasound, elucidating the potential mechanism of this technology."

Airy beams, initially proposed by Sir George Biddell Airy of the Royal Astronomical Society, are unique self-bending waveforms with non-diffracting, self-accelerating, and self-healing properties. Yang Yaoheng, a postdoctoral researcher at Washington University in St. Louis, told China Science Daily, "The characteristics of Airy beams provide opportunities for manipulating ultrasound beams." In 2022, their team designed and 3D-printed an acoustic holographic lens to generate ultrasonic Airy beams, achieving precise and flexible 3D focusing.

Sonogenetics offers researchers a precise method to control the brain, while Airy beam technology enables the shaping and guiding of sound waves to generate arbitrary beam patterns within the brain with high spatial resolution. Hu Zhongtao, Associate Professor at Beihang University School of Medical Science and Engineering, noted, "AhSonogenetics integrates these two technologies, potentially offering an intervention method for neurodegenerative diseases. This approach allows more precise targeting of smaller brain regions compared to traditional methods, and can simultaneously target multiple damaged brain areas."

Initial efficacy in Parkinson's disease treatment

To evaluate the potential of Airy beam holographic sonogenetics in treating Parkinson's disease, researchers designed an "Airy beam holographic sound lens" to generate dual focal points, targeting both sides of the striatum in mouse brains. Yang Yaoheng explained, "Calcium activity is a crucial signal indicating neuronal activation in mouse brains. Using fiber photometry, we integrated Airy beam holographic sonogenetics with calcium recordings in mice, monitoring calcium activity in the left and right striatum during ultrasound stimulation."

Furthermore, the team designed wearable ultrasound devices using Airy beam holographic super-surfaces for non-invasive, cell-type-specific, spatially precise neuroregulation in freely moving mice. Researchers delivered viral vectors containing ultrasound-sensitive ion channels to genetically selected neurons, then used wearable devices to deliver low-intensity focused ultrasound to targeted neurons in the brain.

"Raising temperatures slightly above body temperature activates these ion channels, effectively acting as switches to open or close neurons," Yang Yaoheng said. "Mice models of Parkinson's disease exhibit reduced movement frequency and activity. In our experiments, Airy beam holographic sonogenetics helped enhance the motor aspects and activity frequency of Parkinson's model mice."

Yang Yaoheng added, "The Airy beam holographic sound lens not only generates two focal points but can actually adjust to generate ultrasound waveforms in any desired pattern. The treatment of Parkinson's disease is just one demonstration of its capabilities; future applications could customize acoustic patterns for different brain regions affected by various diseases to enhance therapeutic outcomes."

Future directions of research

Chen Hong's team's research offers new hope for treating Parkinson's disease and other brain disorders. Their development of "Airy beam holographic sonogenetics" integrates sonogenetics and Airy beam technology, achieving precise, non-invasive modulation of specific neurons across multiple brain regions. While current research primarily focuses on mouse models, these preliminary findings demonstrate significant potential for treating neurodegenerative diseases. Moving forward, with further technological development and optimization, AhSonogenetics aims to provide more effective and precise neural modulation therapies, offering promising prospects for patients with brain disorders.

Reference:

Hu Z, Yang Y, Yang L, Gong Y, Chukwu C, Ye D, Yue Y, Yuan J, Kravitz AV, Chen H. Airy-beam holographic sonogenetics for advancing neuromodulation precision and flexibility. Proc Natl Acad Sci U S A. 2024 Jun 25;121(26):e2402200121. doi: 10.1073/pnas.2402200121. Epub 2024 Jun 17. PMID: 38885384.