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.