Non-invasive transcranial ultrasound stimulation for neuromodulation

Author: G Darmani1, T O Bergmann2, K Butts Pauly3, C F Caskey4, L de Lecea5, A Fomenko6, E Fouragnan7, W Legon8, K R Murphy5, T Nandi9, M A Phipps4, G Pinton10, H Ramezanpour11, J Sallet12, S N Yaakub7, S S Yoo13, R Chen14
1 Krembil Research Institute, University Health Network, Toronto, Canada. Electronic address:
2 Neuroimaging Center (NIC), Focus Program Translational Neuroscience (FTN), Johannes Gutenberg University Medical Center, Mainz, Germany; Leibniz Institute for Resilience Research, Mainz, Germany.
3 Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Electrical Engineering, Stanford University, Stanford, CA, USA; Department of Radiology, Stanford University, Stanford, CA, USA.
4 Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
5 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
6 Krembil Research Institute, University Health Network, Toronto, Canada.
7 School of Psychology, University of Plymouth, Plymouth, UK.
8 Department of Neurological Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA.
9 Neuroimaging Center (NIC), Focus Program Translational Neuroscience (FTN), Johannes Gutenberg University Medical Center, Mainz, Germany.
10 Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and the North Carolina State University, Chapel Hill, NC, USA.
11 Centre for Vision Research, York University, Toronto, Ontario, Canada.
12 Univ Lyon, Université Lyon 1, Inserm, Stem Cell and Brain Research Institute, Bron, France; Wellcome Centre for Integrative Neuroimaging, Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
13 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
14 Krembil Research Institute, University Health Network, Toronto, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada. Electronic address:
Conference/Journal: Clin Neurophysiol
Date published: 2021 Dec 31
Other: Volume ID: 135 , Pages: 51-73 , Special Notes: doi: 10.1016/j.clinph.2021.12.010. , Word Count: 263

Transcranial ultrasound stimulation (TUS) holds great potential as a tool to alter neural circuits non-invasively in both animals and humans. In contrast to established non-invasive brain stimulation methods, ultrasonic waves can be focused on both cortical and deep brain targets with the unprecedented spatial resolution as small as a few cubic millimeters. This focusing allows exclusive targeting of small subcortical structures, previously accessible only by invasive deep brain stimulation devices. The neuromodulatory effects of TUS are likely derived from the kinetic interaction of the ultrasound waves with neuronal membranes and their constitutive mechanosensitive ion channels, to produce short term and long-lasting changes in neuronal excitability and spontaneous firing rate. After decades of mechanistic and safety investigation, the technique has finally come of age, and an increasing number of human TUS studies are expected. Given its excellent compatibility with non-invasive brain mapping techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), as well as neuromodulatory techniques, such as transcranial magnetic stimulation (TMS), systemic TUS effects can readily be assessed in both basic and clinical research. In this review, we present the fundamentals of TUS for a broader audience. We provide up-to-date information on the physical and neurophysiological mechanisms of TUS, available readouts for its neural and behavioral effects, insights gained from animal models and human studies, potential clinical applications, and safety considerations. Moreover, we discuss the indirect effects of TUS on the nervous system through peripheral co-stimulation and how these confounding factors can be mitigated by proper control conditions.

Keywords: Neuromodulation; Non-invasive brain stimulation; Plasticity; Transcranial ultrasound stimulation.

PMID: 35033772 DOI: 10.1016/j.clinph.2021.12.010