Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety

Abstract

Ultrasonic neuromodulation is a rapidly growing field, in which low-intensity ultrasound (US) is delivered to nervous system tissue, resulting in transient modulation of neural activity. This review summarizes the findings in the central and peripheral nervous systems from mechanistic studies in cell culture to cognitive behavioral studies in humans. The mechanisms by which US mechanically interacts with neurons and could affect firing are presented. An in-depth safety assessment of current studies shows that parameters for the human studies fall within the safety envelope for US imaging. Challenges associated with accurately targeting US and monitoring the response are described. In conclusion, the literature supports the use of US as a safe, non-invasive brain stimulation modality with improved spatial localization and depth targeting compared with alternative methods. US neurostimulation has the potential to be used both as a scientific instrument to investigate brain function and as a therapeutic modality to modulate brain activity.

Keywords: Brain stimulation; Mechanisms; Neuromodulation; Non-invasive; Safety; Ultrasound.

Fig. 1

Schematic of ultrasound sequences and associated parameters typically utilized for ultrasonic neuromodulation.

Fig. 2

Parameter analysis of central nervous system studies: instantaneous peak pressure (p) against driving frequency (f). The studies are split into human, large animal, small animal and in vitro work. Any studies that conduct histologic analysis and report no damage are filled in blue, and those that report damage are filled in red. Lines of constant mechanical index (MI) and fp², a measure of acoustic radiation force (ARF), are also displayed. (a) Full parameter space (log scale). (b) Subset of parameters applicable to transcranial human delivery (linear scale, p < 1.2 MPa, f < 1.2 MHz). ARF = acoustic radiation force; f = driving frequency; fp² = measure of acoustic radiation forces; MI = constant mechanical index; p = instantaneous peak pressure.

Fig. 3

Parameter analysis of central nervous system studies. For burst wave: burst-averaged intensity (I_SPBA) versus burst duration (BD). For continuous wave: pulse-averaged intensity (I_SPPA) against pulse length (PL). The studies are split into human, small animal and in vitro work. Any studies that conduct histologic analysis and report no damage are filled in blue, and those that report damage are filled in red. Lines of constant energy density (I_SPBA × BD or I_SPPA × PL) are also displayed. (a) Full parameter space (log scale). (b) Subset of parameters (linear scale, I_SPBA / I_SPPA < 30 W/cm², BD / PL < 500 ms). BD = burst duration; E = energy density; I_SPBA = spatial-peak burst-averaged intensity; I_SPPA = spatial-peak pulse-averaged intensity; PL = pulse length.

Fig. 4

Parameter analysis of peripheral nervous system studies. (a) Instantaneous peak pressure (p) against driving frequency (f) with lines of constant mechanical index (MI) and fp², a measure of acoustic radiation force (ARF) (log scale). (b) For burst wave: burst-averaged intensity (I_SPBA) versus burst duration (BD). For continuous wave: pulse-averaged intensity (I_SPPA) against pulse length (PL). Lines of constant energy density (I_SPBA × BD or I_SPPA × PL) are also displayed (log scale). The studies are split into human, small animal and ex vivo work. Any studies that conduct histologic analysis and report no damage are filled in blue, and those that report damage are filled in red. ARF = acoustic radiation force; BD = burst duration; E = energy density; f = driving frequency; fp² = measure of acoustic radiation forces; I_SPBA = spatial-peak burst-averaged intensity; I_SPPA = spatial-peak pulse-averaged intensity; MI = mechanical index; p = instantaneous peak pressure; PL = pulse length.

Fig. 5

Comparison of parameters employed in the central nervous system (CNS, cross) and the peripheral nervous system (PNS, star). (a) Instantaneous peak pressure (p) against driving frequency (f), with lines of constant mechanical index (MI) and fp², a measure of acoustic radiation force (ARF) (log scale). (b) For continuous wave: pulse-averaged intensity (I_SPPA) against pulse length (PL). Lines of constant energy density (I_SPBA × BD or I_SPPA × PL) are also displayed (log scale). ARF = acoustic radiation force; BD = burst duration; CNS = central nervous system; E = energy density; f = driving frequency; fp² = measure of acoustic radiation forces; I_SPBA = spatial-peak burst-averaged intensity; I_SPPA = spatial-peak pulse-averaged intensity; MI = constant mechanical index; p = instantaneous peak pressure; PL = pulse length; PNS = peripheral nervous system.