Noninvasive intervention by transcranial ultrasound stimulation: Modulation of neural circuits and its clinical perspectives

Abstract

Low-intensity focused transcranial ultrasound stimulation (TUS) is an emerging noninvasive technique capable of stimulating both the cerebral cortex and deep brain structures with high spatial precision. This method is recognized for its potential to comprehensively perturb various brain regions, enabling the modulation of neural circuits, in a manner not achievable through conventional magnetic or electrical brain stimulation techniques. The underlying mechanisms of neuromodulation are based on a phenomenon where mechanical waves of ultrasound kinetically interact with neurons, specifically affecting neuronal membranes and mechanosensitive channels. This interaction induces alterations in the excitability of neurons within the stimulated region. In this review, we briefly present the fundamental principles of ultrasound physics and the physiological mechanisms of TUS neuromodulation. We explain the experimental apparatus and procedures for TUS in humans. Due to the focality, the integration of various methods, including magnetic resonance imaging and magnetic resonance-guided neuronavigation systems, is important to perform TUS experiments for precise targeting. We then review the current state of the literature on TUS neuromodulation, with a particular focus on human subjects, targeting both the cerebral cortex and deep subcortical structures. Finally, we outline future perspectives of TUS in clinical applications in psychiatric and neurological fields.

Keywords: low‐intensity focused ultrasound; neuromodulation; noninvasive brain stimulation; transcranial ultrasound stimulation.

Fig. 1

Experimental settings and spatiotemporal characteristics of pulsed ultrasound. (a) Experimental apparatus for transcranial ultrasound stimulation (TUS). A photograph of a TUS system: a transducer, a drive system, and a matching network. The NeuroFUS Pro (Brainbox Ltd) is shown here as an example. (b) Schematic representation of the individual components of a typical TUS system. (c) Temporal characteristics of pulsed ultrasound. (d) Schematic drawing of a transducer and ultrasound beam. In a multi‐element array transducer, focal depth can be adjusted by controlling phasing and power of each element (i.e. axial steering range). The shape of a typical ultrasound focus is ellipsoid. (e) Experiment equipment for TUS: TUS system, magnetic resonance imaging (MRI), neuronavigation system, transcranial magnetic stimulation (TMS), and acoustic simulation.

Fig. 2

Identification of the primary moror cortex (M1) representing the first dorsal interosseous (FDI) and transcranial ultrasound stimulation (TUS) intervention. (a) A finger movement task to identify the FDI representation in the M1. Individuals were instructed to move their left or right FDI at 2 Hz as the arrows blinked for 20 s each, followed by a 20‐s rest. The left–right–rest cycle was repeated six times. (b) Experimental procedures for motor‐evoked potential (MEP) measurements and TUS. MEPs from the right FDI muscle were measured before and after TUS by targeting the identified FDI‐M1 spot via TMS (pre‐TUS and post‐TUS). (c) Brain activation maps during the motor task in representative subjects in the horizontal and parasagittal slices (moving right FDI vs moving left FDI) in the normalized Montreal Neurological Institute space. The FDI‐M1 was located at the cortical surface in one individual (upper panel), whereas the FDI‐M1 was located deep in the central sulcus in another individual (lower panel). Triangles indicate the central sulcus. (d) Distributions of the cortical surface–FDI‐M1 and scalp–cortical surface distances. The black triangle indicates the median of the distribution. (e) Time course of the normalized MEPs before and after TUS. The MEPs were normalized to the pre‐TUS MEPs. A dashed line indicates the baseline MEPs in pre‐TUS. Error bars indicate the standard error of means of the individual. (f) The normalized MEPs before and after TUS. Gray lines indicate data from each individual. *P < 0.05, **P < 0.01, ***P < 0.001, paired t‐test. (a, b, e, f) are adapted from Nakajima et al. (2022). (c, d) are adapted from Osada et al. (2022). A, anterior; cs, central sulcus; L, left; P, posterior; R, right.

Fig. 3

Transcranial ultrasound stimulation (TUS) effects on the basal ganglia for response inhibition. (a) The stop‐signal task consisted of Go (left) and Stop (right) trials. In the Go trials, subjects were instructed to press the left or right button, as indicated by the arrow. In the Stop trials, the left/right arrow was changed to an up‐pointing arrow after the stop‐signal delay, and the subjects were required to withhold their manual response. (b) Group‐level brain activity in the subcortical regions. (c) Three basal ganglia regions targeted by TUS: the subthalamic nucleus (STN), anterior putamen, and posterior putamen in the right hemisphere (upper panels). Regions are shown in coronal and horizontal slices in the normalized Montreal Neurological Institute space. Stop‐signal reaction times (SSRTs) before and after TUS (lower panels). Individuals with shorter SSRTs are considered to be more efficient at response inhibition. Error bars indicate the SEMs. Gray lines indicate data from each individual. **P < 0.01, paired t test. Adapted from Nakajima et al. (2022).