OPIC OPTICS & PHOTONICS International Congress 2023

BISC 2023 | Oral Presentation

Neuroscience
Fri. Apr 21, 2023 3:20 PM - 4:50 PM 419 (Pacifico Yokohama Conference Center)[BISC9-01(Invited)] Toward non-invasive, precise control of internalorgans via ultrasound neuromodulation of theautonomic nervous system
Yizhou Xu1, Kaede Yoshida1, *Yuichi Takeuchi1 （1. Hokkaido University）
Neuromodulation is a technology for reversibly modulating neural activity by applying artificial stimuli to anorganism, and ultrasound neuromodulation is promising with its superior spatial and time resolution. Here webriefly mention the current situation of ultrasound neuromodulation and the neuromodulation of theautonomic nervous system.

©OPTICS & PHOTONICS International Congress

The 9th Biomedical Imaging and Sensing Conference (BISC2023)

BISC9-01(Invited)Toward non-invasive, precise control of internal organs via ultrasoundneuromodulation of the autonomic nervous system
Yizhou Xu, Kaede Yoshida, Yuichi Takeuchi*
Department of Biopharmaceutical Sciences and Pharmacy, Faculty of Pharmaceutical Sciences,
Hokkaido University, Kita 12, Nishi 6, Kita ward, Sapporo, Hokkaido 060-0812, Japan*ytake@pharm.hokudai.ac.jp; phone: +81-11-706-3248; fax: +81-11-706-4987; https://ytake.org

ABSTRACT
Neuromodulation is a technology for reversibly modulating neural activity by applying artificial stimuli to an organism.
Electrical and magnetic stimulation technologies have been employed in clinical practices, especially for brain disorders
including motor and mood disorders. Ultrasound stimulation has theoretically superior spatial and time resolution toelectrical and magnetic stimulation. Even cell-type specific non-invasive neuromodulation is possible with an emerging
technology with mechano-sensitive ion channels. Here we briefly mention the current situation of ultrasoundneuromodulation and the neuromodulation of the autonomic nervous system. An application of the ultrasoundneuromodulation of an organ controlled by the autonomic nervous system (such as the cardiovascular system) is thendiscussed.
Keywords: Neuromodulation, Non-invasive brain stimulation, Ultrasound, Sonogenetics, Autonomic Nervous System,
Cardiovascular system

1. INTRODUCTION
Neuromodulation is a technique for reversibly modulating neural activity by applying artificial stimuli to an organism via
devices or other means. Neuromodulation has made it possible to control drug-resistant cases of brain disorders such as
epilepsy, Parkinson's disease, depression, etc.1 The most commonly used modality of neuromodulation has been
electrical stimulation, which is used clinically as deep brain stimulation or transcranial electrical stimulation. Magnetic
stimulation is also used as transcranial stimulation, especially for modulating symptoms of psychiatric disorders likemajor depressive disorder. However, these modalities have shortcomings such as the invasiveness associated withelectrode insertion, low spatial resolution, and lack of cell-type specificity. Ultrasound is a relatively new modality forneuromodulation that complements the shortcomings of electric and magnetic neuromodulation. It has excellent biopermeability and can be delivered from outside the body (non-invasiveness), stimulus focus can be achieved by focusing
its irradiation from multiple transducers (high spatial resolution), and it has the ability to temporally follow various
stimulation patterns in sub-milliseconds (good temporal resolution). Thus, ultrasound makes it possible to non-invasively
and highly precisely stimulate neuronal nuclei in deep brain structures. Ultrasound neuromodulation can be utilized not
only to control disorders of the central nervous system (CNS), but also to control those of the autonomic nervous system(ANS). Thus, here we briefly review our knowledge of ultrasound neuromodulation and neuromodulation of the ANS.
We then discuss possible applications of ultrasound neuromodulation of the ANS for controlling internal organs, mainly
the heart.

2. ULTRASOUND NEUROMODULATION
Ultrasound can be utilized to modulate neuronal activities in either direct or indirect ways. Firstly, ultrasound candirectly excite or inhibit neuronal activities via modulating mechanosensitive ion channels or lipid bilayers.2 It can open
mechanosensitive ion channels by applying mechanical forces to cell membranes and the cytoskeleton.3,4 Ultrasoundirradiation can modulate the intact brain via endogenous mechanosensitive ion channels such as Piezo channels andtransient receptor potential channels.5, 6 The overexpression of exogenous or endogenous ultrasound-sensitive channels
or other molecules in a defined cell population can enhance the responses of neural activities to ultrasound(sonogenetics).7 Ultrasound may cause small pores of the plasma membrane and it may result in depolarization. Much
research and development has been conducted to utilize ultrasound neuromodulation technologies for controlling brain
disorders such as epilepsy.8

Copyright BISC2023-1-

OPIC OPTICS & PHOTONICS International Congress 2023

The 9th Biomedical Imaging and Sensing Conference (BISC2023)

BISC9-01(Invited)

Ultrasound is also utilized to indirectly modulate neural activities such as brain region-specific drug or gene delivery,
which is mediated by the transient opening of the blood-brain barrier (BBB) with lipid-based microbubbles. Transracialfocused ultrasound stimulation causes contraction and expansion of intravenously administered, ultrasound-sensitive
microbubbles in the brain capillaries, which pushes tight junctions between vascular endothelial cells and transiently
opens the BBB. Currently, this ultrasound-mediated, targeted-drug delivery is under investigation for therapies of
Alzheimer’s disease,9 Parkinson’s disease,10 amyotrophic lateral sclerosis,11 and brain tumors.12, 13 Ultrasound-mediated
BBB opening also enables non-invasive, targeted-gene delivery in small and large brain regions.14, 15

3. NEUROMODULATION OF AUTONOMIC NERVOUS SYSTEM
The ANS maintains the homeostasis of systemic organs and tissue with an extensive network via multiple level reflex
controls. The sympathetic nerve and parasympathetic nerve compose normal autonomic tone with opposite functions andcomplementary ganglia positions. Hence, the selective bilateral modulation of the ANS would redress dysfunctions of
the regulatory circuits and treat disease progression. To date, neuromodulation technologies have allowed attempts tomodulate specific neural circuits to control targeted organs. Vagus nerve stimulation has been revealed as an effective
way for treating inflammation diseases and heart failure.16-18 Baroreflex activation therapy was also tested to relieve
refractory hypertension.19-22 In abdominal targets, vagal nerve blockade has been demonstrated as a therapeutic method
to alleviate obesity.23-26 For lower urinary and digestive tract innervation, sacral nerve stimulation has been used to treat
pelvic dysfunctions such as incontinence.27-29 For chronic stimulation therapy, proper devices with closed-loop control
would improve patient compliance and effects.1, 30, 31 These neuromodulation technologies may be replaced by those withultrasound for enhanced safety and effectiveness.

4. NEUROMODULATION OF CARDIOVASCULAR DISEASES
Sympathetic hyperactivity and parasympathetic hypoactivity underlie many cardiovascular diseases such as hypertension,acute myocardial infarction and heart failure.32-34 Therefore, the imbalance of the ANS can be a therapeutic target. Inbaroreflex activation therapy, the baroreceptors of the carotid sinus nerve would be electrically activated, thensympathetic activity and heart rate would be inhibited via the reflex arc, resulting in a decrease of blood pressure. In
recent years, neuromodulation devices have shown effectiveness and safety in clinical trials for refractory hypertension.22,
35-37
Deep brain stimulation of the midbrain periaqueductal grey has been tested to effectively influence blood pressureand heart rate variability,38-40 which provides a possible therapeutic target. The spinal cord has utility in reducing
sympathetic activity with largely major autonomic ganglia. Spinal cord stimulation in T1-T3 levels has been shown to bea safe and feasible treatment for heart failure41 (but see Zipes et al., 2016).42 Bilateral stellate ganglia innervate the left
ventricle and are remodeled with hypertrophy, inflammation and oxidative stress in cardiomyopathy and ventriculararrhythmia patients. Therefore, bilateral stellectomy (known as cardiac sympathetic denervation) has demonstrated
efficacy in heart failure and refractory ventricular arrhythmia as an intrinsic cardiac neuromodulation.43, 44 Additionally,
renal denervation can decrease abnormal sympathetic afferent activity caused by noradrenaline spillover. Bilateral renal
denervation has been a reported result of reduced arrhythmic burden in several clinical trials.45-47 Cervical vagus nerve
stimulation has substantially elevated the parasympathetic activity and restored autonomic tone balance. However,clinical trials have failed to demonstrate the improvement of heart failure symptoms.48, 49 On the other hand, another
ANTHEM-HF study showed improvements in cardiac function and heart failure symptoms.50-52 Different stimulation
parameters and devices were used in these trials which might explain the variety of efficacy. The tragus is innervated by
the auricular branch of the vagus nerve and this branch enables transcutaneous vagus nerve stimulation from the tragus inhumans.53 The parasympathetic activity was significantly decreased by the tragus stimulation.54 Low-level tragus
stimulation has suppressed atrial fibrillation and decreased inflammatory cytokines in patients.55 In patients withdiastolic dysfunction, left ventricle longitudinal mechanics acutely improved under right tragus stimulation.18
Transcranial-focused ultrasound stimulation targeting the baroreflex circuits, the medulla cardiovascular autonomic
centers, and the vagus nerve itself or its motor nucleus may be a safe and effective therapeutic strategy.

5. CONCLUSION
Here our current knowledge of ultrasound neuromodulation technologies and neuromodulation therapies for ANS
disorders is provided. The ability to non-invasively stimulate neural nuclei deep in the brain is particularly importantbecause it complements the shortcomings of electrical and magnetic stimulation. The implementation of wearable
ultrasound neuromodulation devices combined with the real-time processing of biological signals is also expected to leadto on-demand neural activity intervention methods. These technologies can be combined to implement real-time control

Copyright BISC2023-2-

OPIC OPTICS & PHOTONICS International Congress 2023

The 9th Biomedical Imaging and Sensing Conference (BISC2023)

BISC9-01(Invited)of the cardiac functions via time and organ-specific, transcranial-focused ultrasound stimulation of the medulla
cardiovascular autonomic centers. These topics will be discussed further at the conference.

ACKNOWLEDGEMENTS
This work was supported by AMED (JP21zf0127004, 22gm6510015h0001), KAKENHI (19H03550, 22H04762),
Takahashi Industrial and Economic Research Foundation, the Asahi Glass Foundation, Northern Advancement Center
for Science & Technology of Hokkaido Japan, Takeda Science Foundation, Tateishi Science and Technology Foundation,
the Nagai Foundation Tokyo, Nishinomiya Basic Research Fund Japan, Casio Science Promotion Foundation, andShimazu Science Foundation to Y.T.

REFERENCES[1] Takeuchi, Y., and Berényi, A., “Oscillotherapeutics – Time-targeted interventions in epilepsy and beyond”,
Neurosci. Res. 152, 87-107 (2020).
[2] Yu, K., Niu, X., Krook-Magnuson, E., et al., “Intrinsic functional neuron-type selectivity of transcranial
focused ultrasound neuromodulation.,” Nat. Commun. 12, 2519 (2021).
[3] Kubanek, J., Shukla, P., Das, A., et al., “Ultrasound elicits behavioral responses through mechanical effects onneurons and ion channels in a simple nervous system,” J. Neurosci. 38 (12), 3081-3091 (2018).
[4] Yoo, S., Mittelstein, D. R., Hurt, R. C., et al., “Focused ultrasound excites cortical neurons via
mechanosensitive calcium accumulation and ion channel amplification,” Nat Commun 13, 493 (2022).
[5] Qiu, Z., Guo, J., Kala, S., Zhu, J., et al., “The mechanosensitive ion channel Piezo1 significantly mediates invitro ultrasonic stimulation of neurons,” iScience 21, 448-457 (2019).
[6] Ranade, S. S., Syeda, R., and Patapoutian, A., Mechanically Activated Ion Channels,” Neuron 87 (6), 11621179 (2015).
[7] Wang, S., Meng, W., Ren, Z., et al., “Ultrasonic neuromodulation and sonogenetics: A new era for neuralmodulation,” Front. Physiol. 11, 787 (2020).
[8] Li, X., Yang, H., Yan, J., et al., “Seizure control by low-intensity ultrasound in mice with temporal lobe
epilepsy,” Epilepsy Res. 154, 1-7 (2019)[9] Liu, X., Sta Maria, N. S., Lin S. W., et al., “The applications of focused ultrasound (FUS) in Alzheimer's
disease treatment: A systematic review on both animal and human studies,” Aging Dis. 12(8), 1977-2002(2021).
[10] Gasca-Salas, C., Fernández-Rodríguez, B., Pineda-Pardo, J. A., et al., “Blood-brain barrier opening withfocused ultrasound in Parkinson’s disease dementia,” Nat. Commun. 12, 779 (2021).
[11] Abrahao, A., Meng, Y., Llinas, M., et al. “First-in-human trial of blood–brain barrier opening in amyotrophic
lateral sclerosis using MR-guided focused ultrasound,” Nat. Commun. 10, 4373 (2019).
[12] Mainprize, T., Lipsman, N., Huang, Y., et al. “Blood-brain barrier opening in primary brain tumors with noninvasive MR-guided focused ultrasound: A clinical safety and feasibility study,” Sci. Rep. 9, 321 (2019).
[13] Sun, T., Zhang, Y., Power, C., et al., “Closed-loop control of targeted ultrasound drug delivery across the
blood-brain/tumor barriers in a rat glioma model,” Proc. Natl. Acad. Sci. U. S. A. 114 (48), E10281-E10290(2017).
[14] Ogawa, K., Kato N., Yoshida M., et al., “Focused ultrasound/microbubbles-assisted BBB opening enhances
LNP-mediated mRNA delivery to brain,” J. Control. Release 348, 34-41 (2022).
[15] Nouraein, S., Lee, S., Saenz, V. A., et al., “Acoustically targeted noninvasive gene therapy in large brain
regions,” bioRxiv 2023.01.19.52626 (2023).
[16] Bonaz, B., Sinniger, V., Hoffmann,D., et al., “Chronic vagus nerve stimulation in Crohn's disease: a 6-monthfollow-up pilot study,” Neurogastroenterol. Motil. 28(6), 948-953 (2016).
[17] Koopman, F. A., Chavan, S. S., Miljko, S., et al., “Vagus nerve stimulation inhibits cytokine production andattenuates disease severity in rheumatoid arthritis,” Proc. Natl. Acad. Sci. U. S. A. 113(29), 8284-8289 (2016).
[18] Tran, N., Asad, Z., Elkholey K., et al., “Autonomic neuromodulation acutely ameliorates left ventricular strain
in humans,” J. Cardiovasc. Transl. Res. 12(3), 221-230 (2019).
[19] Wallbach, M., Born, E., Kampfer, D., et al., “Long-term effects of baroreflex activation therapy: 2-year follow-

Copyright BISC2023-3-

OPIC OPTICS & PHOTONICS International Congress 2023

The 9th Biomedical Imaging and Sensing Conference (BISC2023)

BISC9-01(Invited)up data of the BAT Neo system,” Clin. Res. Cardiol. 109(4), 513-522 (2020).
[20] Gordin, D., Fadl Elmula, F. E. M., Andersson, B., et al., “The effects of baroreflex activation therapy on bloodpressure and sympathetic function in patients with refractory hypertension: the rationale and design of theNordic BAT study,” Blood Press., 26(5), 294-302 (2017).
[21] Beige, J., Jentzsch, T., Wendt, R., et al., “Blood pressure after blinded, randomized withdrawal, and resumptionof baroreceptor-activating therapy,” J. Hypertens. 35(7), 1496-1501 (2017).
[22] Bisognano, J. D., Bakris, G., Nadim, M. K., et al., “Baroreflex activation therapy lowers blood pressure inpatients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal
trial,” J. Am. Coll. Cardiol. 58(7), 765-773 (2011).
[23] Camilleri, M., Toouli, J., Herrera, M. F., et al., “Intra-abdominal vagal blocking (VBLOC therapy): clinicalresults with a new implantable medical device,” Surgery 143(6), 723-731 (2008).
[24] Ikramuddin, S., Blackstone, R. P., Brancatisano, A., et al., “Effect of reversible intermittent intra-abdominal
vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial,” JAMA 312(9), 915-922(2014).
[25] Apovian, C. M., Shah, S. N., Wolfe, B. M., et al., “Two-year outcomes of vagal nerve blocking (vBloc) for thetreatment of obesity in the ReCharge Trial,” Obes. Surg. 27(1), 169-176 (2017).
[26] Sarr, M. G., Billington, C. J., Brancatisano, R., et al., “The EMPOWER study: randomized, prospective,
double-blind, multicenter trial of vagal blockade to induce weight loss in morbid obesity,” Obes. Surg. 22(11),1771-1782 (2012).
[27] Dmochowski, R. R. and Gomelsky, A., “Update on the treatment of overactive bladder,” Curr. Opin. Urol.
21(4), 286-290 (2011).
[28] Drake, M. J., Apostolidis, A., Cocci, A., et al., “Neurogenic lower urinary tract dysfunction: Clinicalmanagement recommendations of the neurologic incontinence committee of the fifth international consultation
on incontinence 2013,” Neurourol. Urodyn. 35(6), 657-665 (2016).
[29] Siegel, S. W., Catanzaro, F., Dijkema, H. E., et al., “Long-term results of a multicenter study on sacral nerve
stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention,” Urology, 56(6 Suppl1), 87-91 (2000).
[30] Cracchiolo, M., Ottaviani, M. M., Panarese, A., et al., “Bioelectronic medicine for the autonomic nervous
system: clinical applications and perspectives,” J. Neural. Eng. 18, 041002 (2021).
[31] Yap, J. Y. Y., Keatch, C., Lambert, E., et al., “Critical review of transcutaneous vagus nerve stimulation:
challenges for translation to clinical practice,” Front. Neurosci. 14, 284 (2020).
[32] Krum, H., Schlaich, M., Whitbourn, R., et al., “Catheter-based renal sympathetic denervation for resistant
hypertension: a multicentre safety and proof-of-principle cohort study,” Lancet 373(9671), 1275-1281 (2009).
[33] Cohn, J. N., Levine, T. B., Olivari, M. T., et al., “Plasma norepinephrine as a guide to prognosis in patients withchronic congestive heart failure,” N. Engl. J. Med. 311(13), 819-823 (1984).
[34] La Rovere, M. T., Bigger Jr., J. T., Marcus, F. I., et al., “Baroreflex sensitivity and heart-rate variability inprediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After
Myocardial Infarction) Investigators,” Lancet 351(9101), 478-484 (1998).
[35] de Leeuw, P. W., Bisognano, J. D., Bakris, G. L., et al., “Sustained reduction of blood pressure withbaroreceptor activation therapy: Results of the 6-year open follow-up,” Hypertension 69(5), 836-843 (2017).
[36] Wilks, S. J., Hara, S. A., Ross, E. K., et al., “Non-clinical and pre-clinical testing to demonstrate safety of the
Barostim neo electrode for activation of carotid baroreceptors in chronic human implants,” Front. Neurosci. 11,
438 (2017).
[37] Weaver, F. A., Abraham, W. T., Little, W. C., et al., “Surgical experience and long-term results of baroreflex
activation therapy for heart failure with reduced ejection fraction,” Semin. Thorac. Cardiovasc. Surg. 28(2),320-328 (2016).
[38] Sverrisdottir, Y. B., Green, A. L., Aziz, T. Z., et al., “Differentiated baroreflex modulation of sympathetic nerve
activity during deep brain stimulation in humans,” Hypertension 63(5), 1000-1010 (2014).
[39] Pereira, E. A., Lu, G., Wang, S., et al., “Ventral periaqueductal grey stimulation alters heart rate variability inhumans with chronic pain,” Exp. Neurol. 223(2), 574-581 (2010).
[40] Green, A. L., Wang, S., Owen, S. L., et al., “Deep brain stimulation can regulate arterial blood pressure in
awake humans,” Neuroreport 16(16), 1741-1745 (2005).
[41] Tse, H. F., Turner, S., Sanders, P., et al., “Thoracic spinal cord stimulation for heart failure as a restorative
treatment (SCS HEART study): first-in-man experience,” Heart Rhythm, 12(3), 588-595 (2015).

Copyright BISC2023-4-

OPIC OPTICS & PHOTONICS International Congress 2023

The 9th Biomedical Imaging and Sensing Conference (BISC2023)

BISC9-01(Invited)[42] Zipes, D. P., Neuzil, P., Theres, H., et al., “Determining the feasibility of spinal cord neuromodulation for thetreatment of chronic systolic heart failure: The DEFEAT-HF Study,” JACC Heart Fail. 4(2), 129-136 (2016).
[43] Vaseghi, M., Gima, J., Kanaan, C., et al., “Cardiac sympathetic denervation in patients with refractory
ventricular arrhythmias or electrical storm: intermediate and long-term follow-up,” Heart Rhythm 11(3), 360366 (2014).
[44] Vaseghi, M., Barwad, P., Malavassi Corrales, F. J., et al., “Cardiac sympathetic denervation for refractory
ventricular arrhythmias,” J. Am. Coll. Cardiol. 69(25), 3070-3080 (2017).
[45] Armaganijan, L. V., Staico, R., Moreira, D. A., et al., “6-Month outcomes in patients with implantablecardioverter-defibrillators undergoing renal sympathetic denervation for the treatment of refractory ventriculararrhythmias,” JACC Cardiovasc. Interv. 8(7), 984-990 (2015).
[46] Ukena, C., Mahfoud, F., Ewen, S., et al., “Renal denervation for treatment of ventricular arrhythmias: datafrom an international multicenter registry,” Clin. Res. Cardiol. 105(10), 873-879 (2016).
[47] Remo, B. F., Preminger, M., Bradfield, J., et al., “Safety and efficacy of renal denervation as a novel treatmentof ventricular tachycardia storm in patients with cardiomyopathy,” Heart Rhythm, 11(4), 541-546 (2014).
[48] Gold, M. R., Van Veldhuisen, D. J., Hauptman, P. J., et al., “Vagus nerve stimulation for the treatment of heart
failure: The INOVATE-HF Trial,” J. Am. Coll. Cardiol. 68(2), 149-158 (2016).
[49] Zannad, F., De Ferrari, G. M., Tuinenburg, A. E., et al., “Chronic vagal stimulation for the treatment of low
ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF)
randomized controlled trial,” Eur. Heart J. 36(7), 425-433 (2015).
[50] Premchand, R. K., Sharma, K., Mittal, S., et al., “Autonomic regulation therapy via left or right cervical vagus
nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial,” J. Card. Fail. 20(11),808-816 (2014).
[51] DiCarlo, L. A., Libbus, I., Kumar, H. U., et al., “Autonomic regulation therapy to enhance myocardial functionin heart failure patients: the ANTHEM-HFpEF study,” ESC Heart Fail. 5(1), 95-100 (2018).
[52] Nearing, B. D., Libbus, I., Amurthur, B., et al., “Acute autonomic engagement assessed by heart rate dynamics
during vagus nerve stimulation in patients with heart failure in the ANTHEM-HF trial,” J. Cardiovasc.
Electrophysiol. 27(9), 1072-1077 (2016).
[53] Fallgatter, A. J., Neuhauser, B., Herrmann, M. J., et al., “Far field potentials from the brain stem after
transcutaneous vagus nerve stimulation,” J. Neural. Transm. (Vienna) 110(12), 1437-1443 (2003).
[54] Clancy, J. A., Mary, D. A., Witte, K. K., et al., “Non-invasive vagus nerve stimulation in healthy humans
reduces sympathetic nerve activity,” Brain Stimul. 7(6), 871-877 (2014).
[55] Stavrakis, S., Humphrey, M. B., Scherlag, B. J., et al., “Low-level transcutaneous electrical vagus nerve
stimulation suppresses atrial fibrillation,” J. Am. Coll. Cardiol. 65(9), 867-875 (2015).

Copyright BISC2023-5-

OPIC OPTICS & PHOTONICS International Congress 2023