(I-360) Multi-Element Random Array Ultrasound Transducers: A Novel Tool for Precise and Safe Neuromodulation in Rodent and Non-human Primate Models

Introduction:: Transcranial focused ultrasound (tFUS) neuromodulation is a non-invasive technique that uses focused ultrasound waves to modulate neural activities in targeted brain regions, thus causing the neural tissue to undergo a mechanical deformation, which can change neuronal activities. While tFUS has proved advantages of being non-surgical, spatial specific, and deep penetration over conventional approaches, e.g., deep brain stimulation or transcranial magnetic/current stimulation, there are strong rising needs from the neuroscience research and clinical applications for enhancing targeting precision and stimulation efficacy of tFUS. Multi-element ultrasound scheme is a technological solution to meet such needs, and the random array configuration provides further opportunities to deliver uniform and efficient acoustic energy to the brain target.

Conventional ultrasound arrays use regular patterns, e.g., linear, spiral and radial arrangements of transducer elements, which lead to interference patterns and hotspots in the acoustic field. This inevitably causes uneven energy delivery to the target tissue, potentially leading to unwanted ancillary neural activations or even tissue damage. In contrast, a random array ultrasound transducer (RAUT) adopts irregular distributions of transducer elements, thus allowing for a more uniform energy distribution of the acoustic field, resulting in more targeted and effective neuromodulation. Furthermore, random ultrasound arrays provide more flexibility and adaptability in designing and optimizing the transmitted acoustic field for specific animal models and/or brain targets.


Materials and Methods:: Computer simulations based on Sim4Life P-Acoustics (Zürich MedTech AG, Switzerland) were implemented to study and compare the array patterns and fundamental frequencies in generating focused ultrasound pressure field in free water or in the presence of specific skull models. After the simulation assessments, two 128-element RAUT probes, H275 for large brain models and H276 for small rodent models were manufactured by Sonic Concepts (Bothell, WA, USA).

To characterize the ultrasound transmission performance and delineate temporal and spatial dynamics near the brain targets, a three-dimensional ex vivo pressure mapping system was developed, which employed a needle hydrophone (HNR500, Onda Corporation, Sunnyvale, CA USA) submerged in water and driven by a 3-axial positioning stage (Velmex, Inc., Bloomfield, NY, USA) to map the spatial-temporal pressure/intensity field of ultrasound after an ex vivo skull bone. The needle hydrophone was placed beneath an ex vivo skull and measured ultrasound pressure values at discrete locations (scanning resolution: 0.5 mm) behind the skull. Rodent skulls for testing with H276 were freshly dissected from euthanized animals, while a real non-human primate (NHP) skull for testing with H275 were acquired from Skulls Unlimited International, Inc. (Oklahoma City, OK, USA). This setup allowed us to quantify the transmitted energy versus that was delivered through the skull, which generated the characterizations of ultrasound insertion lose due to the presence of a certain skull model at a specific fundamental frequency. This scanning system can also mimic the in vivo ultrasound setup with the same sonication site, collimator location and incidence angle.


Results, Conclusions, and Discussions:: Results

The highly focused 128-element RAUT (H275, element diameter: 4 mm) working at a fundamental frequency (f₀) of 700 Hz (-3 dB operating band: 648 – 777 kHz, a concave radius of 35 mm, f-number: 0.58) is developed (Fig. 1a). By simulating the focused ultrasound in free water, the measured coherent axial and lateral resolutions (-6dB contour) are 5.61 mm and 1.89 mm, respectively (Fig. 1b). Both dimensions are further measured as 6.13 mm and 2.15 mm, respectively in degassed water (Fig. 1c-d). In the presence of a fully hydrated monkey skull immersed in degassed water, the transcranial ultrasound focus is spatially tight with a focal size of 2.67 mm laterally and 7.71 mm axially (-6dB contour) (Fig. 1e-f). The acoustic insertion loss is measured as approximately -9.1 dB.

The H276 with an element diameter of 0.8 mm (1-mm pitch) is featured with an acoustic aperture radius of 8.5 mm (Fig. 2a-b, f-number: 0.57, f₀: 1.5 MHz, −3dB operating band: 1.35-1.60 MHz). In free water, the measured coherent axial and lateral focal sizes (−3 dB contour) are 1.36 mm and 0.46 mm, respectively (Fig. 2c-e). In the presence of a freshly excised mouse skull immersed in degassed water, the transcranial ultrasound focus is free of aberration with a lateral specificity of 0.84 mm and an axial specificity of 1.71 mm (−3 dB contour) (Fig. 2f). The acoustic insertion loss is measured as approximately -10.3 dB.

Conclusions

In conclusion, the study describes and presents a novel approach to enhance targeting precision and stimulation efficacy of tFUS neuromodulation using RAUT probes. The ex-vivo pressure mapping system and computer simulations confirm the performance of these probes without the need of phase aberration corrections.

Discussions

This present work on tFUS neuromodulation using RAUTs has demonstrated promising results in enhancing targeting precision and stimulation efficacy. The use of multi-element ultrasound schemes, particularly random array configurations, allows for more uniform ultrasound energy distribution and flexibility in designing and optimizing the transmitted acoustic field for specific animal models and brain targets, thus potentially reducing the risk of unwanted neural activations or tissue damage.


Acknowledgements (Optional): : This work was supported in part by NIH U18 EB029354 and R01 NS124564.


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