Similar to all non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) (Maizey et al., 2013), transcranial ultrasound stimulation (TUS) has a low risk of adverse reactions. Legon et al. (2020) published results from a report of symptoms questionnaire from 64 participants who took part in 7 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, all of which were initially reported 20 minutes after TUS. No new symptoms were reported upon follow up. 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.
Legon, W., et al. (2020). A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. Sci Rep 10(1): 5573. URL: https://pubmed.ncbi.nlm.nih.gov/32221350/
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. The two main measures related to inertial cavitation are Isppa (spatial peak pulse average) and the mechanical index (MI). In contrast, the two measures of heating during an ultrasound are the thermal index (TI) and the Ispta (spatial peak temporal average).
Glossary of Terms
Studies have monitored tissue temperature non-invasively during thalamic stimulation using magnetic resonance (MR) thermometry and confirmed the absence of tissue damage using histological examination. Dallapiazza et al., (2018) aimed to demonstrate the effects of low-intensity focused ultrasound (LIFU) for neuromodulation and mapping in the thalamus of large-brain animals. Ten swine were used, and LIFU was applied to different thalamic nuclei while monitoring somatosensory evoked potentials (SSEPs). The results showed that LIFU selectively modulated neuronal activity without causing tissue damage or heating. High spatial resolution allowed for precise targeting of specific thalamic nuclei. These findings suggest that LIFU can safely modulate neuronal circuits and may be applicable for non-invasive brain mapping in humans.
TUS Safety Considerations
In neuromodulatory transcranial focused ultrasound (tFUS) studies, the use of an effective intensity limit of 3 mW/cm2 is a common upper limit for Ispta (Lee et al., 2016b) and 30 mW/cm2 is an approximate Isppa limit (Pasquinelli et al., 2019; Tyler et al., 2018).
The FDA standard for diagnostic ultrasound stimulation (US) also require protocol-specific estimations of transcranial ultrasound stimulation (TUS) parameters prior to human stimulation (Pasquinelli et al., 2019). It is critical that the passage of the ultrasonic beam through the human cranium, is modelled prior to stimulation, so that these safety parameters can be estimated ahead of human stimulation.
The MATLAB k-Wave toolbox can be utilised as an essential step in this progress. It can be used to model the propagation of the ultrasonic wave through the skull for TUS applications (Mueller et al., 2017).
The ultrasonic wave can be absorbed and cause heating when it interacts with the skull. Additionally, the skull can weaken the ultrasonic waveform, and the degree of attenuation depends on the bone density along the path of the 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.
Pinton et al., (2012) aimed to quantify the attenuation, scattering, and thermal absorption in bone. Using a numerical algorithm and measurements from various instruments, the researchers demonstrated that absorption contributes minimally to attenuation, with reflection, scattering, and mode conversion being the primary factors. The measured absorption coefficients for longitudinal and shear waves in cortical bone are 2.7 dB/cm and 5.4 dB/cm, respectively. This information allows for estimating heat deposition based on the acoustic field. Pichardo et al. (2011) investigated the relationship between skull bone density, speed of sound, and attenuation coefficient for ultrasound in the brain. Measurements were taken on human calvaria specimens at different frequencies, revealing frequency-dependent variations in density. The study reported average values of speed of sound and attenuation coefficient for cortical and trabecular bone at different frequencies, while also noting the absence of measurable radiation force at certain frequencies. Pichardo et al. (2017) also aimed to understand ultrasound transmission through the human skull for improved imaging and therapeutic applications. Using a viscoelastic wave equation model, they correlated computed tomography data with shear speed of sound. Validated with plastic plates, their model accurately predicted sound propagation. With optimised functions, they successfully predicted transcranial ultrasound transmission at different frequencies. The findings from these studies emphasise the importance of voxel-level information for understanding skull ultrasound transmission and provide insights into the complex behavior of ultrasound in bone and its implications for medical applications, particularly in terms of attenuation mechanisms and the relationship between bone density, speed of sound, and attenuation coefficient.
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 mW/cm2 (Tyler et al., 2018). 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.
- Ultrasound neuromodulation: a review of results, mechanisms and safety. Blackmore, J., Shrivastava, S. and Sallet, J., et al. Ultrasound in medicine and biology 45(7): 1509-1536. (2019)
- Non-invasive neuromodulation and thalamic mapping with low intensity focused ultrasound. Dallapiazza, R.F., et al. Journal of Neurosurgery 128(3): 875-884. (2018)
- Histologic safety of transcranial focused ultrasound neuromodulation and magnetic resonance acoustic radiation force imaging in rhesus macaques and sheep. Gaur, P., et al. Brain Stimulation 13(3): 804-814. (2020)
- Image-guided focused ultrasound-mediated regional brain stimulation in sheep. Lee, W., et al. Ultrasound Med Biol 42(2): 459-470. (2016a)
- Transcranial focused ultrasound stimulation of human primary visual cortex. Lee, W., et al. Scientific Reports 6(34026). (2016b)
- A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. Legon, W., et al. Sci Rep 10(1): 5573. (2020)
- Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation. Miazey, L., et al. Clin Neurophysiol 124(3): 536-544. (2013)
- Numerical evaluation of the skull for human neuromodulation with transcranial focused ultrasound. Mueller, J.K., Ai, L., Bansal, P. and Legon, W. J Neural Eng 14(6). (2017)
- Safety of transcranial focused ultrasound stimulation: A systematic review of the state of knowledge from both human and animal studies. Pasquinelli, C., Hanson, L.G. and Siebner, H.R., et al. Brain Stimulation 12(6): 1367-1380. (2019)
- A viscoelastic model for the prediction of transcranial ultrasound propagation: application for the estimation of shear acoustic properties in the human skull. Pichardo, S., Moreno, C. and Drainville, A., et al. Phys Med Biol 62(17): 6938-6962. (2017)
- Multi-frequency characterisation of the speed of sound and attenuation coefficient for longitudinal transmission of freshly excised human skulls. Pichardo, S., Sin, V.W. and Hynynen, K. Phys Med Biol 56(1): 219-250. (2011)
- Attenuation, scattering, and absorption of ultrasound in the skull bone. Pinton, G., Aubry, J.F. and Bossy, E. et al. Med Phys 3991): 299-307. (2012)
- Ultrasonic modulation of neural circuit activity. Tyler, W.J., Lani, S.W. and Hwang, G.M. Curr Opin Neurobiol 50: 222-231. (2018)
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