From Rigid to Conformable Miniaturized Focused Ultrasound Neurostimulators

Low-intensity focused ultrasound (LIFU) was discovered to have an excitatory effect in neuronal circuits approximately 15 years ago. Ever since that seminal work was published [1], hundreds of researchers worldwide have continuously investigated LIFU for brain stimulation, both for neuroscience and clinical translation. The reason for the excitement around LIFU is apparent: the low absorption and scattering together with the millimetric wavelengths of ultrasound in soft tissues, such as the brain, means that ultrasound can be transmitted from a distance, such as from the surface of the skull or brain, and be accurately focused with a neuromodulatory dosage in a millimetric spot anywhere in the brain, without affecting nor damaging the neurons in the propagation path [2]. Consequently, LIFU can be a happy medium between the precision of electrical deep brain stimulation and the non-invasiveness of transcranial magnetic stimulation while potentially having a considerably higher benefit-risk ratio [3]. The fact that there are currently ~100 clinical trials exploring LIFU for diseases such as Parkinson’s, Alzheimer’s, and Treatment Resistant Depression further showcases the great potential of this neuromodulation technology.<br/>In the past 15 years, however, focused ultrasound transducer technology has not accompanied the fast developments of LIFU discoveries. These transducers, which generate focused ultrasound waves, still have a handheld/helmet bulky-form factor and require benchtop electronics [2]. Consequently, they are not compatible with the scales of rodents for pre-clinical research, are prohibitively large, and are power inefficient for use as a wearable LIFU neurostimulator.<br/>Similar to the developments we saw in electrical stimulation, where large electrodes and bulky implantable pulse generators (IPGs) are being miniaturized into chip form factors, the field of ultrasound transducer technology is demanding the same revolution. In this talk, I will describe my group’s efforts towards this goal by focusing on novel ultrasound transducer microfabrication and microsystem integration methods and next-generation ultrasound electronics for two specific cases: full monolithic integration of ultrasound transducers on top of the integrated electronic chips for maximum level of miniaturization towards freely-moving experiments in rodents [4-6]; integration of ultrasound transducers and electronic chips in flexible substrates for large-aperture conformable ultrasonic neurostimulators, for deep brain stimulation in humans.<br/><br/>[1] Tyler WJ, Tufail Y, Finsterwald M, Tauchmann ML, Olson EJ, et al. (2008) Remote Excitation of Neuronal Circuits Using Low-Intensity, Low-Frequency Ultrasound. PLOS ONE 3(10): e3511.<br/>[2] Joseph Blackmore, Shamit Shrivastava, Jerome Sallet, Chris R. Butler, Robin O. Cleveland, Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety, Ultrasound in Medicine & Biology, Volume 45, Issue 7, 2019,<br/>[3] Beisteiner R. Human Ultrasound Neuromodulation: State of the Art. Brain Sci. 2022 Feb 1;12(2):208.<br/>[4] T. Costa, C. Shi, K. Tien, J. Elloian, F. A. Cardoso and K. L. Shepard, "An Integrated 2D Ultrasound Phased Array Transmitter in CMOS With Pixel Pitch-Matched Beamforming," in <i>IEEE Transactions on Biomedical Circuits and Systems</i>, vol. 15, no. 4, pp. 731-742, Aug. 2021<br/>[5] Chen Shi <i>et al. </i>Application of a sub–0.1-mm3 implantable mote for in vivo real-time wireless temperature sensing.Sci. Adv.7,eabf6312(2021)<br/>[6] Javid A, Ilham S, Kiani M. A Review of Ultrasound Neuromodulation Technologies. IEEE Trans Biomed Circuits Syst. 2023 Oct;17(5):1084-1096.