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Radiation Force As a Physical Mechanism for Ultrasonic Neurostimulation of the Ex Vivo Retina

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Radiation Force As a Physical Mechanism for Ultrasonic Neurostimulation of the Ex Vivo Retina This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. A link to any extended data will be provided when the final version is posted online. Research Articles: Systems/Circuits Radiation force as a physical mechanism for ultrasonic neurostimulation of the ex vivo retina Mike D. Menz1, Patrick Ye2, Kamyar Firouzi3, Amin Nikoozadeh3, Kim Butts Pauly4, Pierre Khuri-Yakub5 and Stephen A. Baccus1 1Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, 94305, USA 2Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA 3E. L. Ginzton Laboratory, Stanford University, Stanford, CA, 94305, USA 4Department of Radiology, Stanford University, Stanford, CA, 94305, USA 5Department of Electrical Engineering, Stanford University, Stanford, CA, 94305, USA https://doi.org/10.1523/JNEUROSCI.2394-18.2019 Received: 17 September 2018 Revised: 23 May 2019 Accepted: 30 May 2019 Published: 13 June 2019 Author contributions: M.D.M., P.Y., A.N., K.P., P.T.K.-Y., and S.A.B. designed research; M.D.M., P.Y., and A.N. performed research; M.D.M. and K.F. analyzed data; M.D.M. wrote the first draft of the paper; M.D.M. and S.A.B. edited the paper; M.D.M. and S.A.B. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. This work was supported by a grant from the NIBIB and the Stanford Neurosciences Institute. We thank M. Maduke, M. Prieto, J. Kubanek, D. Palanker and J. Brown for helpful discussions. Corresponding and Submitting author: Mike D. Menz, [email protected], Stanford University, Fairchild Bldg., 299 Campus Dr. W, Stanford, CA, 94305-5101, USA Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.2394-18.2019 Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2019 the authors 1 Radiation force as a physical mechanism for ultrasonic 2 neurostimulation of the ex vivo retina 3 Abbrev. Title: Ultrasound stimulates retina by radiation force 4 Mike D. Menz1, Patrick Ye2, Kamyar Firouzi3, Amin Nikoozadeh3, Kim Butts Pauly4, Pierre 5 Khuri-Yakub5, Stephen A. Baccus1 6 7 1Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, 94305, 8 USA 9 2Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA 10 3E. L. Ginzton Laboratory, Stanford University, Stanford, CA, 94305, USA 11 4Department of Radiology, Stanford University, Stanford, CA, 94305, USA 12 5Department of Electrical Engineering, Stanford University, Stanford, CA, 94305, USA 13 Corresponding and Submitting author: Mike D. Menz, [email protected], Stanford 14 University, Fairchild Bldg., 299 Campus Dr. W, Stanford, CA, 94305-5101, USA 15 16 Paper statistics (based on clean copy): 58 total pages, 48 pages of text, 10 figures, 1 movie 17 #Words: Abstract = 246, Introduction = 537, Significance statement = 109, Discussion = 2668 18 19 Acknowledgements: This work was supported by a grant from the NIBIB and the Stanford 20 Neurosciences Institute. We thank M. Maduke, M. Prieto, J. Kubanek, D. Palanker and J. Brown 21 for helpful discussions. 22 Conflict of Interest: The authors will be listed as inventors on a provisional patent application 23 for a PIRF neural stimulator effective once the paper is accepted for publication. 1 24 25 Abstract 26 Focused ultrasound has been shown to be effective at stimulating neurons in many animal 27 models, both in vivo and ex vivo. Ultrasonic neuromodulation is the only non-invasive 28 method of stimulation that could reach deep in the brain with high spatial-temporal 29 resolution, and thus has potential for use in clinical applications and basic studies of the 30 nervous system. Understanding the physical mechanism by which energy in a high acoustic 31 frequency wave is delivered to stimulate neurons will be important to optimize this 32 technology. We imaged the isolated salamander retina of either sex during ultrasonic 33 stimuli that drive ganglion cell activity and observed micron scale displacements, consistent 34 with radiation force, the nonlinear delivery of momentum by a propagating wave. We 35 recorded ganglion cell spiking activity and changed the acoustic carrier frequency across a 36 broad range (0.5 - 43 MHz), finding that increased stimulation occurs at higher acoustic 37 frequencies, ruling out cavitation as an alternative possible mechanism. A quantitative 38 radiation force model can explain retinal responses and could potentially explain previous 39 in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo. Finally, we 40 found that neural activity was strongly modulated by the distance between the transducer 41 and the electrode array showing the influence of standing waves on the response. We 42 conclude that radiation force is the dominant physical mechanism underlying ultrasonic 43 neurostimulation in the ex vivo retina and propose that the control of standing waves is a 44 new potential method to modulate these effects. 45 46 Significance Statement 2 47 Ultrasonic neurostimulation is a promising noninvasive technology that has potential for both 48 basic research and clinical applications. The mechanisms of ultrasonic neurostimulation are 49 unknown, making it difficult to optimize in any given application. We studied the physical 50 mechanism by which ultrasound is converted into an effective energy form to cause 51 neurostimulation in the retina and find that ultrasound acts through radiation force leading to a 52 mechanical displacement of tissue. We further show that standing waves have a strong 53 modulatory effect on activity. Our quantitative model by which ultrasound generates radiation 54 force and leads to neural activity will be important in optimizing ultrasonic neurostimulation 55 across a wide range of applications. 56 57 Introduction 58 Ultrasonic neuromodulation has been demonstrated in the brains of human (Lee et al., 2015; 59 2016a; Legon et al., 2014; Monti et al., 2016), monkey (Wattiez et al., 2017; Deffieux et al., 60 2013), sheep (Lee et al., 2016b), rat (Younan et al., 2013), mouse (Li et al., 2016; Ye et al., 2016; 61 King et al., 2014; King et al., 2012; Tufail et al., 2010; Tyler et al., 2008), and retina of 62 salamander (Menz et al., 2013) and rat (Jiang et al., 2018). The capability of ultrasound to reach 63 any brain structure noninvasively through the skull, and the highly developed technology to 64 deliver ultrasound make this approach promising both for basic studies of neural function and 65 clinical applications. Yet results in different preparations have varied, including both excitatory 66 and inhibitory effects. The development of this approach would benefit greatly from a 67 quantitative understanding of the mechanisms of ultrasonic neuromodulation, allowing the 68 process to be optimized in terms of efficacy of stimuli, efficiency and spatiotemporal distribution 69 of effects. 3 70 71 In the process of transduction of a stimulus into a biological response, one can distinguish the 72 physical mechanism such as acoustic pressure or thermal energy from the biophysical 73 mechanism that senses that energy, including changes in membrane capacitance or particular 74 ionic channels. Here we focus on the physical mechanism by which an acoustic wave is 75 converted into an effective stimulus for a neuron, a process that is currently not understood. The 76 leading candidates for physical mechanism are radiation pressure, the process by which an 77 absorbed or reflected wave delivers momentum, and cavitation, which includes the stable or 78 unstable formation of bubbles, creating a mechanical disturbance, and thermal energy. 79 80 Radiation force is a nonlinear effect proportional to the acoustic wave amplitude, thus creating a 81 continuous, non-oscillating force for a stimulus of constant amplitude (Rudenko et al., 1996). By 82 this mechanism a carrier wave with a frequency too high to have a direct biological effect can be 83 converted into a low frequency mechanical force with dynamics of the envelope of the wave. 84 When radiation force is exerted on a liquid, this results in bulk flow of fluid known as acoustic 85 streaming. Tissue attenuation increases with carrier frequency, therefore radiation force and also 86 heating will increase with frequency. 87 88 Cavitation can occur if the acoustic pressure wave becomes sufficiently negative, causing gas 89 bubbles to form that oscillate at the carrier frequency (Nightingale et al., 2015). Inertial 90 cavitation occurs when those oscillations change in size and eventually burst the bubble, creating 91 a destructive violent event. In stable cavitation the bubble does not burst and is hypothesized to 4 92 produce safe neuromodulation. Cavitation is less likely at higher carrier frequencies because it 93 becomes more difficult to sustain oscillations in the bubble. 94 95 In this study we use optical imaging to measure displacements in the retina and vary the acoustic 96 frequency to test which of these mechanisms is most likely. We find that ultrasonic stimulation 97 in the retina is consistent with a model whereby radiation force produced micron-scale 98 mechanical displacements. The acoustic frequency dependence is consistent with radiation force 99 but inconsistent with cavitation. In addition, we see that standing waves influence the effects of 100 ultrasound. We conclude that radiation force is the primary physical mechanism for ultrasound to 101 stimulate the retina. 102 103 Materials & Methods 104 Experimental Design and Statistical Analysis 105 We conducted several different types of experiments for the purpose of established whether 106 radiation force is the dominant physical mechanism responsible for ultrasonic neurostimulation, 107 the details of these experiments are described below in the appropriate sub-sections. In terms of 108 experimental design, our goal is to use at least two retinas from two different salamanders and 109 record from at least 30 ganglion cells for electrophysiology experiments.
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