The Body Acoustic: Ultrasonic Neuromodulation for Translational Medicine

Abstract

For the greater part of the last century, ultrasound (US) has seen widespread use in applications ranging from materials science to medicine. The history of US in medicine has also seen promising success in clinical diagnostics and regenerative medicine. Recent studies have shown that US is able to manipulate the nervous system, leading toward potential treatment for various neuropathological conditions, a phenomenon known as ultrasonic neuromodulation (NM). Ultrasonic NM is a promising alternative to pharmaceuticals and surgery, due to high spatiotemporal resolution combined with the potentially noninvasive means of application. Current advances have made progress in establishing effective dosage limits, waveform parameters, and stimulus regimes in order to achieve desired effects in a variety of tissue and cell types. However, to date there has been limited systematic analysis of the complex variables involved in creating a therapeutic US stimulation regime specifically tailored to the nervous system. Without a fundamental understanding of the effects of US on neural tissue, including the surrounding bone, musculature, and vasculature, the safety and efficacy of US as an NM tool is yet to be determined. Advances in imaging technology and focusing hardware highlight new avenues for potential clinical applications for therapeutic ultrasonic stimulation. US may be an alternative to electrical and magnetic means of NM for targets in the central nervous system as well as in the peripheral and autonomic nervous systems. This review provides a historical perspective on the past, present, and future of US as a translational therapeutic.

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease—A New Navigated Focal Brain Therapy

“…[2,13,24,27] The likely basis are mechanical effects on cell membranes affecting mechanosensitive ion channels and generating membrane pores. Several principles, related to different ultrasound-based techniques, have been proposed.…”

The effects of low intensity focused ultrasonic stimulation on dorsal root ganglion neurons and Schwann cells in vitro

“…In the BLS model, the oscillating pressure waves act upon the lipid bilayer of cell membranes. The alternating high‐ and low‐pressure regions of the traveling waveforms caused by noninertial cavitation of gas bodies acts upon the membrane in a manner similar to a person jumping on a trampoline, as the membrane deflects up and down relative to the wave's path (Krasovitski, Frenkel, Shoham, & Kimmel, 2011; Plaksin, Shoham, & Kimmel, 2014; Ventre & Koppes, 2016). The resulting changes in strain of the membrane in turn act upon proteins and channels imbedded within the membrane.…”

“…Current gold standard surgical methods of peripheral nerve injury (PNI) repair have subpar rates of full functional recovery cited at 51% for motor and 43% for sensory (Grinsell & Keating, 2014). Furthermore, the severity of the nerve injury, typically proportional to the size of the injury gap in instances of nerve transection, is inversely proportional to the likelihood of functional recovery (Deumens et al., 2010; Lee & Wolfe, 2000; Ventre & Koppes, 2016). Other issues with surgical interventions for PNI include the fact that the surgery is technically difficult, availability of obtaining donor nerves is limited, and surgical complications such as infection, bleeding, and the development of neuropathy are possible (Chang & Hsu, 2004; Dellon & Mackinnon, 1988; Deumens et al., 2010; Lundborg, 2003; Millesi, 1967; Ventre, Puzan, Ashbolt, & Koppes, 2018).…”

“…Other issues with surgical interventions for PNI include the fact that the surgery is technically difficult, availability of obtaining donor nerves is limited, and surgical complications such as infection, bleeding, and the development of neuropathy are possible (Chang & Hsu, 2004; Dellon & Mackinnon, 1988; Deumens et al., 2010; Lundborg, 2003; Millesi, 1967; Ventre, Puzan, Ashbolt, & Koppes, 2018). Prior work highlighted the disparity between the prevalence of PNI and the efficacy of current treatments (Grinsell & Keating, 2014; Sunderland, 1951; Ventre & Koppes, 2016; Ventre et al., 2018). As such, we have begun investigating the potential of ultrasound stimulation (US) to facilitate nerve regeneration in PNI.…”

Transcranial Pulse Stimulation with Ultrasound in Alzheimer’s disease – A new navigated focal brain therapy

“…Regarding the precise mechanisms, specifically how ultrasound may affect neurons and generate neuroplastic effects, current knowledge is limited. Several principles, related to different techniques, have been proposed (Tyler et al 2018, Miller and O'Callaghan 2017, Ventre and Koppes 2016, Bystritsky and Korb 2015. They include pore formations in cell membranes (Babakhanian et al 2018), increases in extracellular serotonin and dopamine levels (Min et al 2011), reduction of GABA levels (Yang et al 2012), increase of brain-derived neurotrophic factor (BDNF), glial cell linederived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) (Lin et al 2015).…”