Like all non-invasive brain stimulation techniques, Transcranial Ultrasound Stimulation (TUS) (also referred to as Transcranial-focused ultrasound Stimulation (tFUS), Low-Intensity Focused Ultrasound Stimulation (LIFUS), Focused Ultrasound Stimulation (FUS) and Focused Ultrasound Neuromodulation (FUN)), has a low risk of adverse reactions (see Maizey et al., 2013, for an example in transcranial magnetic stimulation) (TMS). Legon et al. (2020) published the results of a report of symptoms questionnaire from 64/120 participants who took part in seven TUS experiments. 7/64 reported mild to moderate symptoms that were ‘possibly’ or ‘probably’ related to the application of TUS, including, muscle twitches, problems with attention, anxiety and neck pain which were reported 20 minutes after, but not after 1 week to a month after the application of Transcranial Focused Ultrasound. A graph showing the number of participants who reported adverse reactions following TUS, along with the likelihood of it being related to sonication can be found in figure 1 below.
There are two major routes by which TUS has the potential to become harmful: inertial cavitation (mechanical effect) and heating (thermal effect). Inertial cavitation takes place when vapour cavities (or “bubbles”) form in soft tissue. Under certain conditions, these cavities can collapse rather than oscillate, which creates undesired force and affects neighbouring tissue. There are two measures related to inertial cavitation: 1) Isppa, which is the spatial peak pulse average, which is the average intensity calculated at the point in space of the spatial maximum, and is measured in units of Watts per cm²; and 2) the mechanical index (MI), which provides an estimate of the likelihood of inertial cavitation. In contrast, there are two different measures of heating during an ultrasound: 1) the thermal index (TI) which measures temperature increases in soft tissues; and 2) the spatial peak temporal average intensity (Ispta), which refers to the average intensity of energy across time at the point in space where energy absorption from the ultrasonic beam is greatest. Ispta is measured in units of Watts per cm². Some experiments have monitored tissue temperature non-invasively during thalamic stimulation using MR thermometry and confirmed the absence of tissue damage using histological examination (Dallapiazza et al., 2017).
(Figure 1: A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. Legon W, Adams S, Bansal P, Patel PD, Hobbs L, Ai L, Mueller JK, Meekins G, & Gillick BT. Scientific Reports. March 2020)
TUS Safety Considerations
In Transcranial Focused Ultrasound studies for neuromodulation, an effective intensity limit of 3 mW/cm2 tends to be used as an upper limit for Ispta (Lee et al., 2016) whereas 30 mW/cm2 is a rough Isppa limit (Pasquinelli et al., 2019; Tyler, 2019). Pasquinelli et al. (2019) point out that the FDA standard for diagnostic US also requires protocol-specific estimations of TUS parameters prior to human stimulation. It is critical that the passage of the ultrasonic beam through the human cranium is modelled prior to stimulation, so these safety parameters can be estimated ahead of human stimulation. The MATLAB k-Wave toolbox is essential here, which has already successfully been used to model the propagation of the ultrasonic wave through the skull for TUS applications (see Mueller et al., 2017, for details on estimating skull properties for TUS).
The skull can absorb a lot of energy from the ultrasonic wave, which can result in heating. The skull can also attenuate the ultrasonic waveform and the extent of this attenuation is determined by the bone density of the skull in the path of ultrasonic wave (Tyler et al., 2018). The impact of bone density on neuromodulation re-affirms the necessity of modelling the passage of an ultrasonic wave through a human skull to develop safe but participant-specific dosing methods for TUS. It is possible to monitor skull temperature online using magnetic resonance thermometry (Ozenne et al., 2020; Dallapiazza et al., 2018). Such an approach has revealed that changes in temperature are limited to the skull and only ranged between 1 and 2 degrees Celcius (Ozenne et al., 2020). Thus the combination of Transcranial Focused Ultrasound and MRI could guarantee that a TUS protocol is not causing dangerous rises in skull temperature in real-time.
A critical variable that needs to be considered is the inter-stimulus interval (ISI) when devising safe TUS protocols. So far an ISI of 7 – 12 seconds has not been associated with any damage (Tyler, 2019). An ISI of 7 seconds is much larger than the 1-second ISI associated with tissue damage in the form of a microhemorrhage (Lee et al., 2016). However, a recent paper has addressed the concerns raised by Lee et al. (2016). Gaur et al. (2020) used the TUS protocol used by Lee et al. (2016) and compared the histological evidence of subjects treated with TUS with a control group who were not treated with TUS. Gaur et al. revealed no difference in the amount of parenchymal red blood cell extravasation in TUS-treated subjects compared to control subjects. This suggests that the evidence of damage was a post-mortem artefact rather than a consequence of TUS application.
Current recommendations for low-intensity Transcranial Focused Ultrasound are the application of short pulses (ranging from 0.02 to 100ms) at a moderate to high repetition frequency (ranging from 10Hz – 2kHz) with a low duty cycle (< 50%), along with an Isppa that is less than 30 W/cm2 as starting point ahead of further studies clarifying the safe use of TUS (Tyler, 2019). The use of MATLAB tools to model bone density in addition to careful consideration and investigation of low-intensity TUS parameters will enable the unprecedented spatial resolution of TUS to be utilised to safely understand neural circuitry and its implications for cognition, physiology and behaviour.
- Histologic safety of transcranial focused ultrasound neuromodulation and magnetic resonance acoustic radiation force imaging in rhesus macaques and sheep. Pooja Gaur, Kerriann M Casey, Jan Kubanek, Ningrui Li, Morteza Mohammadjavadi, Yamil Saenz, Gary H Glover, Donna M Bouley, Kim Butts Pauly. Brain Stimulation. June 2020
- A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans.. Legon W, Adams S, Bansal P, Patel PD, Hobbs L, Ai L, Mueller JK, Meekins G, & Gillick BT. Scientific Reports. March 2020
- MRI monitoring of temperature and displacement for transcranial focus ultrasound applications. Ozenne V, Constans C, Bour P, Santin MD, Valabrègue R, Ahnine H, Pouget P, Lehéricy S, Aubry JF, & Quesson B. Neuroimage. January 2020
- Safety of transcranial focused ultrasound stimulation: A systematic review of the state of knowledge from both human and animal studies. Pasquinelli C, Hanson LG, Siebner HR, Lee HJ, & Thielscher A. Brain Stimulation. December 2019
- Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety. Blackmore, J., Shrivastava, S., Sallet, J., Butler, C. R., & Cleveland, R. O.. Ultrasound in Medicine & Biology. July 2019
- Ultrasonic modulation of neural circuit activity. Tyler WJ, Lani SW, & Hwang GM. Current Opinion in Neurobiology. June 2018
- Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound. Dallapiazza RF, Timbie KF, Holmberg S, Gatesman J, Lopes MB, Price RJ, Miller GW, & Elias WJ.. Journal of Neurosurgery. March 2018
- Numerical evaluation of the skull for human neuromodulation with transcranial focused ultrasound. Mueller JK, Ai L, Bansal P, & Legon W. Journal of Neural Engineering. December 2017
- Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation. Maizey L, Allen CP, Dervinis M, Verbruggen F, Varnava A, Kozlov M, Adams RC, Stokes M, Klemen J, Bungert A, Hounsell CA, & Chambers CD. Clinical Neurophysiology. March 2013
- Non-invasive transcranial ultrasound stimulation for neuromodulation. G. Darmani, T.O. Bergmann, K. Butts Pauly, C.F.Caskey, L. de Lecea, A. Fomenko, E. Fouragnan, W. Legon, K.R. Murphy, T. Nandi, M.A. Phipps, G. Pinto, H. Ramezanpour, J. Sallet, S.N. Yaakub, S. S. Yoop, R.Chen. Clinical Neurophysiology. March 2022
- Transcranial focused ultrasound stimulation of human primary visual cortex. Wonhye Lee, Hyun-Chul Kim, Yujin Jung, Yong An Chung, In-Uk Song, Jong-Hwan Lee & Seung-Schik Yoo. Scientific Reports 6. September 2016
The following products from our catalogue are associated with this technique. To find out more about these supported devices, follow the links below or get in touch via email or phone.