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Ultrasonic Neuromodulation Causes Widespread Cortical Activation via an Indirect Auditory Mechanism

Sato, Tomokazu and Shapiro, Mikhail G. and Tsao, Doris Y. (2018) Ultrasonic Neuromodulation Causes Widespread Cortical Activation via an Indirect Auditory Mechanism. Neuron, 98 (5). pp. 1031-1041. ISSN 0896-6273. PMCID PMC8127805. doi:10.1016/j.neuron.2018.05.009.

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Ultrasound has received widespread attention as an emerging technology for targeted, non-invasive neuromodulation based on its ability to evoke electrophysiological and motor responses in animals. However, little is known about the spatiotemporal pattern of ultrasound-induced brain activity that could drive these responses. Here, we address this question by combining focused ultrasound with wide-field optical imaging of calcium signals in transgenic mice. Surprisingly, we find cortical activity patterns consistent with indirect activation of auditory pathways rather than direct neuromodulation at the ultrasound focus. Ultrasound-induced activity is similar to that evoked by audible sound. Furthermore, both ultrasound and audible sound elicit motor responses consistent with a startle reflex, with both responses reduced by chemical deafening. These findings reveal an indirect auditory mechanism for ultrasound-induced cortical activity and movement requiring careful consideration in future development of ultrasonic neuromodulation as a tool in neuroscience research.

Item Type:Article
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URLURL TypeDescription CentralArticle Paper
Shapiro, Mikhail G.0000-0002-0291-4215
Tsao, Doris Y.0000-0003-1083-1919
Additional Information:© 2018 Elsevier Under an Elsevier user license. Available online 24 May 2018. The authors thank Hubert Lim, Hongsun Guo, and Sangjin Yoo for helpful discussions and input on the manuscript, and members of the Shapiro and Tsao labs for assistance with experiments. This research was supported by NIH BRAIN Initiative grant R24MH106107 (Co-PIs D.Y.T. and M.G.S.) and the Howard Hughes Medical Institute (D.Y.T.). Related research in the Shapiro Laboratory is also supported by the Heritage Medical Research Institute and the Packard Fellowship in Science and Engineering. Data and Software Availability: All data are available upon reasonable request to DYT ( or MGS ( Author Contributions: T.S., M.G.S., and D.Y.T. conceived the study. T.S. designed and performed all experiments and analyzed the data. T.S., M.G.S., and D.Y.T. interpreted the results and wrote the manuscript. Declaration of Interests: D.Y.T. and M.G.S. declare no competing interests. T.S. is an inventor on the following patents relating to neuromodulation technologies: (1) US20120283502A1 Ultrasound neuromodulation treatment of depression and bipolar disorder, (2) US20130144192A1 Ultrasound neuromodulation treatment of anxiety (including panic attacks) and obsessive-compulsive disorder, (3) US20130197401A1 Optimization of ultrasound waveform characteristics for transcranial ultrasound neuromodulation, (4) US20140148872A1 Wearable transdermal electrical stimulation devices and methods of using them, (5) US20140194726A1 Ultrasound Neuromodulation for Cognitive Enhancement, (6) US20140211593A1 Method and system for direct communication, (7) US20150135840A1 Systems and devices for coupling ultrasound energy to a body, (8) US20150174418A1 Device and Methods for Noninvasive Neuromodulation Using Targeted Transcranial Electrical Stimulation, (9) US20160008632A1 Methods and apparatuses for networking neuromodulation of a group of individuals, (10) US20160038770A1 Focused transcranial ultrasound systems and methods for using them, (11) US20170080255A1 Thin and wearable ultrasound phased array devices, (12) WO2014127091A1 Transcranial ultrasound systems, and (13) WO2014130960A1 Methods and apparatuses for networking neuromodulation of a group of individuals, and corresponding World and regional patents. However, all patents are assigned to Neurotrek Inc., Thync Inc., and Cerevast Inc., which author T.S. does not hold any financial interest or advisory, consulting, or board position in. All holding rights and financial interest belong to the aforementioned companies; author T.S. does not hold any of the aforementioned patents.
Group:Heritage Medical Research Institute
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
Subject Keywords:ultrasound; neuromodulation; auditory cortex; cortical calcium imaging; cross modal sensory interactions
Issue or Number:5
PubMed Central ID:PMC8127805
Record Number:CaltechAUTHORS:20180108-132355264
Persistent URL:
Official Citation:Tomokazu Sato, Mikhail G. Shapiro, Doris Y. Tsao, Ultrasonic Neuromodulation Causes Widespread Cortical Activation via an Indirect Auditory Mechanism, Neuron, Volume 98, Issue 5, 2018, Pages 1031-1041.e5, ISSN 0896-6273, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84167
Deposited By: George Porter
Deposited On:08 Jan 2018 21:33
Last Modified:24 May 2021 18:18

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