An implantable piezoelectric ultrasound stimulator (ImPULS) for deep brain activation
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1.
California Institute of Technology
Abstract
Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO3]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.
Copyright and License
© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Acknowledgement
This work was supported by MIT Media Lab Consortium funding. J.F.H. was supported by NIH Neurobiological Engineering Training Program Grant #5T32EB019940. K.A.C. was supported by the BCS Alder (1972) Graduate Student Fellowship and the National Science Foundation Graduate Research Fellowship. C.D. thanks to her late aunt, Dogrucan Caliskanoglu, who lost her life due to brain cancer in 2012, for inspiring this work since then. We thank Dr. Hyunsu Park for technical discussions and assistance with piezoelectric microfabrication. The authors would also like to thank Sophia Shen for assistance with microfabrication and Marine Kaufmann for assistance with mouse surgery and perfusion. We would like to thank the lab members of Conformable Decoders: Colin Marcus, Jin-hoon Kim, Aastha Shah, and David Sadat for scientific discussion and manuscript review, Dr. Fernando Fernandez from Boston University for discussion about Calcium imaging, and Dr. Kenji Shibata from SCIOCS Company Limited, Sumitomo Chemical group, Japan for discussion about KNN. This work was performed in part at the MIT.nano.
Contributions
These authors contributed equally: Jason F. Hou, Md Osman Goni Nayeem.
C.D. conceived the research idea, designed research methodology and aims, and directed all research activities. C.D., J.F.H., and M.O.G.N. designed the experiments. H.E.D. provided insights on device design parameters. J.F.H. and M.O.G.N. fabricated the devices, performed the characterization of devices and performed COMSOL multiphysics simulation. E.C-H performed in vitro primary neuron experiments and hydrophone measurements. S.B.O. assisted in adaptive voltage experiments for accelerated aging and fatigue tests. B.W., J.F.H., and M.O.G.N. performed the 2-p Imaging & Slice experiment ex vivo. E.A.R., A.C.-M., J.F.H., M.O.G.N., and M.S. performed the in vivo cFos experiments. K.A.C., J.F.H., M.O.G.N., and A.A.P. performed the in vivo dopamine (fiber photometry) experiment. J.F.H., M.O.G.N., K.A.C., E.A.R., A.C.-M., E.C.-H., and B.W. contributed in data analysis with the input from J.A.W., M.G.S., F.W., S.R., and C.D. All the authors contributed to writing the manuscript. C.D. supervised the overall project.
Data Availability
All data supporting the findings of this study are available within the article and its supplementary files but can be found at https://doi.org/10.6084/m9.figshare.25571583. Any additional requests for information can be directed to, and will be fulfilled by, the corresponding authors. Source data are provided with this paper.
Code Availability
All code supporting the findings of this study will be made available upon request to the corresponding authors. Custom code and documentation is provided at https://doi.org/10.5281/zenodo.11094313.
Conflict of Interest
The authors declare no competing interests.
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Additional details
- PMCID
- PMC11150473
- Massachusetts Institute of Technology
- National Institutes of Health
- NIH Predoctoral Fellowship 5T32EB019940
- National Science Foundation
- NSF Graduate Research Fellowship
- Caltech groups
- Tianqiao and Chrissy Chen Institute for Neuroscience