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.

Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked

“…75 In neurostimulation research it is well accepted that confounding factors have to be 76 carefully controlled [33] in order to ensure that the effects observed are indeed the result of 77 having stimulated a certain brain area, rather than by extraneous effects such as 78 somatosensory stimulation [34,35]. In TUS this is particularly important since the precise 79 mechanisms by which neuromodulation occurs are not well understood, although these 80 remain the subject of intense research efforts [36]. It is important therefore to determine 81 whether TUS may also have auditory side-effects in humans that could impact outcomes.…”

“…1d). 124 Both acoustic and thermal participant-specific modelling was carried out to determine 125 appropriate source locations and amplitudes in order to focus to the intended targets as well 126 as satisfy the safety constraints (maximum peak modelled pressure in CSF or brain tissue = 127 0.6 MPa, maximum temperature rise in skull bone = 3 •C, maximum temperature rise in brain 128 tissue = 1 •C) similar to other studies involving human subjects (see Fig 2 of Ref [36]). 129 Numerical modelling was carried out using k-Wave, a pseudospectral time domain solver [39].…”

Sonogenetics for noninvasive and cellular-level neuromodulation in rodent brain

“…Compared with electric, magnetic, optical, and chemical stimuli that have been used by existing neuromodulation technologies, focused ultrasound (FUS) offers unique advantages as it can noninvasively deliver ultrasound energy through the intact human scalp and skull deep into the brain and focus at cortical areas 1,2 as well as deep brain areas 3 with high spatial selectivity. Existing FUS neuromodulation techniques use ultrasound pulses with low intensity to produce mechanical effects for neural and behavioral modulation with a negligible temperature increase 4 . Numerous studies have confirmed that FUS can noninvasively modulate neural activity and brain function in animal models 5,6 and humans 1,3 .…”

“…The major challenge in the development of sonogenetics is to find suitable actuators. Sonogenetics was initially proposed by Ibsen et al 9 where ultrasound 4 selectively activated the cells expressing a mechanosensitive ion channel in Caenorhabditis elegans. However, ultrasound alone did not affect the behavior of the worm.…”

Thermodynamic state of the interface during acoustic cavitation in lipid suspensions

“…Cavitation is the formation of vapor cavities in a liquid due to a tensile stress (1) and is assumed to be one of the key mechanisms for biophysical effects of ultrasound and in particular shock waves (2,3). It has been suggested as a possible mechanism both in transmembrane and intracellular drug delivery (4) as well as acoustic excitation of the peripheral nervous system (5). The key biophysical system in both these cases is the cellular membrane, which is essentially a self-assembled macromolecular bilayer mainly composed of lipids.…”