Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Noninvasive Neuromodulation of Peripheral Nerve Pathways Using Ultrasound and Its Current Therapeutic Implications Christopher Puleo and Victoria Cotero GE Global Research, Niskayuna, NY 12309 Correspondence: [email protected] This review describes work from several research groups in which ultrasound is being used to target the peripheral nervous system and perform neuromodulation noninvasively. Although these techniques are in their infancy compared to implant-based and electrical nerve stim- ulation, if successful this new noninvasive method for neuromodulation could solve many of the challenges facing the field of bioelectronic medicine. The work outlined herein shows results in which two different (potentially therapeutic) targets are stimulated, a neuroimmune pathway within the spleen and a nutrient/sensory pathway within the liver. Both data and discussion are provided that compare this new noninvasive technique to implant-based nerve stimulation. PERIPHERAL NERVE STIMULATION Rapoport 2016; Guzman-Negron and Goldman AND NEUROMODULATION 2017; Johnson and Wilson 2018). In the past 10 years, peripheral nerve stimulation has under- eripheral nerve stimulation has been used to gone a “renaissance” with standard tools (such Ptreat neuropathic pain since the 1960s, and as cervical vagus nerve stimulation [VNS]) be- over the last 20 years has developed into a major ing tested in clinical trials, in which the target of clinical and industrial market. Traditionally, stimulation are end-organ nerve reflexes that implantable electronic devices have been used, modulate molecular (and not neuromuscular) www.perspectivesinmedicine.org and the primary clinical applications have been targets (Marchall et al. 2015; Pavlov and Tracey treatment of severe and chronic pain (in place of 2015; Willemze et al. 2015; Yuan and Silberstein invasive surgical procedures or opioid treat- 2016; Chavan et al. 2017). This novel use of ment) (Slavin 2008; Wolter 2014; Chakravarthy medical devices to target specific physiological et al. 2016; Meier 2017). Until recently, second- or molecular pathways (similar to drugs) is ary use (or testing) in applications beyond pain known as bioelectronic medicine (Tracey 2016; management has been limited to other neural Olofsson and Tracey 2017). or neuromuscular conditions and pathologies, In one recent clinical trial, VNS has been including migraine headaches, depression, epi- applied to stimulate a neural reflex that inhibits lepsy, and urinary incontinence (Schuster and the production of cytokines (i.e., an inflamma- Editors: Valentin A. Pavlov and Kevin J. Tracey Additional Perspectives on Bioelectronic Medicine available at www.perspectivesinmedicine.org Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a034215 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press C. Puleo and V. Cotero tory reflex) (Koopman et al. 2016). Preclinical fund.nih.gov/Sparc; www.darpa.mil/program/ studies have shown that this reflex is dependent electrical-prescriptions) have recently made it a on a vagus nerve signal that reaches the spleen, goal to enable precise end-organ neuromodula- alters concentration of norepinephrine and ace- tion (in which specific signals are sent to a single tylcholine, and modulates the release and pro- organ to affect its physiological function). Addi- duction of cytokines by resident (and migrating) tional, corporate funding entities (i.e., GSK- macrophages (Borovikova et al. 2000; Tracey Google, GE-Feinstein) (fortune.com/2016/08/ 2009, 2016). One of the main cytokines under 01/google-alphabet-glaxosmithkline-bioelec regulation by this reflex is tumor necrosis factor tronics; www.innovateli.com/ge-brings-good- (TNF). Interestingly, TNF is the target of bio- things-bioelectronics-research) have also taken logic therapies that inhibit TNF signaling in up this challenge, with an intent to eventually rheumatoid arthritis ([RA] and other chronic decode the language of communication between inflammatory disease) patients (Koopman et al. nerves and organs, and to learn to modulate the 2016). In RA, symptomatic relief can be achieved signals to create novel therapies. However, pre- in up to 50% of patients using anti-TNF biolog- cision stimulation and neuromodulation with ics, and recently a first-of-its-kind study has implant technologies remains an unsolved chal- shown that VNS significantly inhibited TNF lenge, as smaller devices (i.e., those that can be production for up to 84 days in a pilot study in implanted closer to a target organ) remain in RA patients (with a concomitant decrease in dis- development (Mei and Irazoqui 2014). Alterna- ease severity as measured by standardized clin- tive methods for axon-level specific modulation ical composite scores) (Koopman et al. 2016). remain confined to experimental molecular and These first studies have been rapidly followed genetic techniques (such as optogenetics [Deis- by a series of observations and discoveries of seroth 2015] or nanoparticle-based approaches local nerve reflexes modulating the output of an [Temel and Jahanshahi 2015]). In addition, the end-organ or gland. Many of these new discov- optimal stimulation tools and parameters for eries provides the opportunity for therapeutic clinical use remain unknown. It is improbable replacement or augmentation of a drug therapy. that the same level or type of neuromodulation These latest studies include discovery of a sciatic/ is required to effect end-tissue function at differ- vagus pathway that modulates production of ent organ targets. What are the basal neural sig- immune-modulating catecholamines from the nalsrequiredfor homeostasis withinthese differ- adrenal gland (Torres-Rosas et al. 2014), a group ent natural reflexes, and which are activated only of peripheral sensory pathways that convey met- in response to a specific external stimulus or as- abolic information (i.e., nutrient concentrations, sociated with disease pathogenesis? What are the www.perspectivesinmedicine.org gut-derived satiety signals and adiposity-related optimal parameters to specifically stimulate the hormones) to the brain for maintenance of en- local nerve reflex, and how many times should ergy and glucose homeostasis (Roh et al. 2016), stimulation take place to generate this therapeu- and a local intestinal nerve circuit required to tic effect without any nonbeneficial side effects? activate tissue protective gene expression pro- Answers to these (and other) questions are nec- grams in resident macrophages upon bacterial essary to build new tools that provides both pre- infection (Gabanyi et al. 2016). Each of these dis- cision stimulation (i.e., modulation of specific coveries carries implications on the neural com- end organs and physiological functions) and ponents involved with maintenance of tissue/ paths toward clinical translation. organ homeostasis, and potentially the patho- In this review, we first summarize work genesis of tissue/organ related chronic diseases. from a group of researchers who have begun to However, development of therapeutic tech- uniquely apply ultrasound energy within organs niques from these important discoveries requires to provide a form of precision neuromodulation significant investment in future research and de- (Gigliotti et al. 2013; Cotero et al. 2019; Zachs velopment. Several research investment entities et al. 2019). We discuss what is known about the (i.e., NIH SPARC; DARPA ElectRx) (common use of ultrasound in these neuromodulation 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a034215 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Neuromodulation of Peripheral Nervous Pathways Using Ultrasound applications, and how it compares to current NEW INSIGHTS INTO THE USE forms of electrical stimulation techniques. We OF NONINVASIVE ULTRASOUND show some direct comparisons between the NEUROMODULATION TECHNIQUES ultrasound and implant-based electrical stimu- lation techniques (used within the same pre- Attempts at using ultrasound stimuli to elicit and clinical models of disease) (Cotero et al. 2019). alter action potential propagation in ex vivo Finally, we offer some commentary on general nerves date back to the 1980s (Schelling et al. lessons learned from this use of ultrasound and 1994). In these initial studies, the ultrasound how it might be applied to continue develop- energy was focused on the same large nerves (out- ment of more precise and clinically impactful side of the organ or targettissue) that traditionally neuromodulation technologies. host implanted electrodes (e.g., the cervical vagus nerve), and this strategy has produced many conflicting results. While some studies TECHNICAL CHALLENGES IN ACHIEVING report that ultrasound was capable of eliciting PRECISION NEUROMODULATION action potentials in ex vivo nerves (Wright WITH CURRENT NONINVASIVE et al. 2017), others have shown that ultrasound TECHNOLOGIES energy is only capable of modifying electrically For VNS, the first approaches used to develop induced action potentials (Colucci et al. 2009). noninvasive stimulation protocols (i.e., tools ca- Many of the reports demonstrating ultrasound- pable