Like all non-invasive brain stimulation techniques, transcranial focused ultrasound (tFUS) 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 tFUS experiments. 7/64 reported mild to moderate symptoms that were ‘possibly’ or ‘probably’ related to the application of tFUS, 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 tFUS. A graph showing the number of participants who reported adverse reactions following tFUS, along with the likelihood of it being related to sonication can be found below.
There are two major routes by which tFUS 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 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).
TUS Safety Considerations
In tFUS 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 tFUS 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 tFUS applications (see Mueller et al., 2017, for details on estimating skull properties for tFUS).
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 tFUS. 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 tFUS and MRI could guarantee that a tFUS 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 tFUS 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 (Lee et al., 2016). Current recommendations for low intensity tFUS 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 tFUS (Tyler, 2019). The use of MATLAB tools to model bone density in addition to careful consideration and investigation of low intensity tFUS parameters will enable the unprecedented spatial resolution of tFUS to be utilized to safely understand neural circuitry and its implications for cognition, physiology and behaviour.
- 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
- 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
- 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
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