What is transcranial ultrasound stimulation?
Transcranial ultrasound stimulation (TUS) is a novel and captivating approach to non-invasive modulation of neural circuits within the intact human brain. Variations of TUS include techniques such as transcranial focused ultrasound stimulation (tFUS), focused ultrasound neuromodulation (FUN), low-Intensity focused ultrasound stimulation (LIFUS) and transcranial pulse stimulation (TPS). These techniques surpasses the capabilities of transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (tES) in terms of superior spatial resolution and depth of stimulation.
Why is TUS more accurate than other methods of non-invasive brain stimulation?
Both transcranial electrical stimulation (tES) and transcranial magnetic stimulation (TMS) have inherent limitations regarding the accuracy and depth of stimulation they can achieve. When employing tES, the current is impeded by the skull, resulting in only a fraction of the total applied current reaching the intended cortical site. Although TMS can unveil the timing of neural processes with reasonable spatial resolution, it faces a trade-off between depth and accuracy. Stimulating deeper regions of the brain compromises spatial resolution.
In contrast, transcranial-focused ultrasound (tFUS) neuromodulation introduces a novel approach to modulating neural circuits using acoustic mechanisms. Transcranial ultrasound stimulation (TUS) involves generating an acoustic wave through piezoelectricity, where electrical current passes through a crystal, inducing vibrations that release energy through an ultrasound transducer (Darmani et al., 2022). The design of the TUS transducer enables precise focusing of acoustic energy on a specific spatial point. This capability allows the acoustic wave to be concentrated at unprecedented depths beneath the cortical surface while maintaining high spatial resolution without any loss.
Applications and Effects of TUS
The precise targeting capability of transcranial-focused ultrasound (tFUS) has expanded the range of brain areas eligible for non-invasive brain stimulation research. This advancement has allowed investigations into the causal functional significance of regions like the visual cortex, anterior cingulate cortex (ACC), thalamus, and amygdala.
Deffieux et al., (2013) tested the feasibility of using low-intensity focused ultrasound (FUS) to modulate brain function in awake macaque monkeys. The results showed that FUS significantly affected behaviour, specifically the latency of antisaccade tasks. Wattiez et al., (2017) also investigated the effects of low-intensity transcranial ultrasonic stimulation (TUS) on neuronal discharge in awake behaving monkeys. The results showed significant modulation of neuronal activity in the supplementary eye field (SEF) during TUS compared to control stimulation. Both studies support the use of FUS for non-invasive modulation of brain activity with high spatial resolution.
An illustrative example in the real world involves utilising TUS to explore the involvement of the ACC in representing the value of choices that are not immediately made but could potentially be made in the future. Additionally, these investigations have shed light on whether such representations influence the selection of alternative choices in the future (Fouragnan et al., 2019). Khalighinejad et al., (2019) also explored the factors influencing decisions about whether and when to act in macaques. They found that the ACC and basal forebrain track contextual factors, such as cues indicating reward rates and previous action decisions, and impact behaviour in different ways. Using tFUS, the researchers effectively altered activity in these areas and observed changes in the timing of action decisions.
Furthermore, an additional study conducted a 40-second application of TUS and observed a significant impact on the connectivity pattern of the ACC with interconnected regions (Folloni et al., 2019). This effect persisted for approximately one hour following the stimulation. Importantly, the spatial distribution of these effects, as measured by functional magnetic resonance imaging (fMRI), corresponded to the areas where the acoustic wave was estimated to have the greatest intensity based on computed tomography (CT) scans. Utilising the same TUS protocol, Verhagen et al., (2019) discovered that the stimulation altered the selective interaction between stimulated areas and the rest of the brain. TUS effects were observed in specific medial frontal brain regions and the meningeal compartment, but they were temporary and did not involve microstructural changes.
TUS on M1 and S1
TUS is used to study the motor and somatosensory systems by non-invasively modulating neural activity, providing insights into motor behaviour, sensory perception, and brain function.
Fomenko et al., (2020) investigated the effects of low-intensity TUS on motor cortex activity in healthy subjects. TUS safely suppressed motor cortical activity and improved reaction time on a visuomotor task. The effects were influenced by different acoustic parameters, such as sonication duration and duty cycle. TUS also increased intracortical inhibition. Legon et al., (2018b) also investigated the impact of TUS on human motor cortical excitability and behaviour using a novel paradigm combining ultrasound and magnetic stimulation. The results showed that ultrasound inhibited motor responses, attenuated certain neural processes, and improved reaction time in a behavioural task. Both studies provided new insights into the effects of TUS on motor function and supports its potential as a neuromodulatory technique.
tFUS can be used to modulate human brain function in the primary somatosensory cortex (S1) (Legon et al., 2014). tFUS can attenuate somatosensory evoked potentials and modulate sensory-evoked brain oscillations. Legon et al., (2014) showed these effects were localised to the targeted S1 region and improved sensory discrimination without affecting attention or response bias.
Recent studies have explored the advantages of combining EEG with transcranial focused ultrasound (TUS) for non-invasive brain assessment and modification. Lee et al., (2015) investigated TUS effects on the somatosensory cortex, observing tactile sensations and specific EEG potentials in healthy individuals. Safety assessments showed promising results, suggesting the potential of image-guided TUS for localised brain stimulation. Lee et al., (2017) developed a method establishing a remote brain link between individuals, using TUS to generate tactile sensations based on one person's motor task. This brain-to-brain interface opens possibilities for expanded communication. Additionally, Mueller et al., (2014) utilised a computational model to understand ultrasound's impact on brain dynamics. EEG recordings revealed spatially specific modulation of cortical activity, primarily in the beta frequency range. The skull's role in enhancing ultrasound focusing further supports its potential for targeted neuromodulation. Together, EEG and TUS offer valuable insights into brain function modulation and hold promise for non-invasive assessment and modification of region-specific brain activity.
Another neuroimaging modality that has been used as a guidance of tFUS applications is magnetic resonance imaging (MRI). tFUS under MRI guidance provides valuable monitoring capabilities for safer and more precise targeting of brain structures. Ozenne et al., (2020) used a novel MRI-pulse sequence to measure displacement and temperature changes in different brain regions. The sequence effectively localised the acoustic focus and visualised heating near the skull. Fast frame rate imaging addressed breathing-related artifacts. The results demonstrate the potential clinical utility of this approach for improving therapy precision and safety.
Is transcranial ultrasound stimulation safe?
As with all non-invasive brain stimulation methods, transcranial ultrasound stimulation (TUS) does have a small potential risk of adverse reactions in subjects. A thorough exploration of all of the potential side effects of TUS can be found on our TUS Safety page.
What is Transcranial Focused Ultrasound Stimulation?
Dr Lennart Verhagen (Donders Institute) provides a clear introduction to TUS techniques in this free webinar.
An Introduction to the Physics of Transcranial Ultrasound Stimulation
In this Brainbox Initiative webinar, Kyle Morrison of Sonic Concepts, Inc. explores the physics behind TUS.
- Non-invasive neuromodulation and thalamic mapping with low intensity focused ultrasound. Dallapiazza, R.F., et al. Journal of Neurosurgery 128(3): 875-884. (2018)
- Non-invasive transcranial ultrasound stimulation for neuromodulation. Darmani, G., et al. Clinical Neurophysiology 135: 51-73Clinical Neurophysiology 135: 51-73. (2022)
- Low-intensity focused ultrasound modulates monkey visuomotor behaviour. Deffieux, T., et al. Curr Biol 23(23): 2430-2433. (2013)
- Manipulation of subcortical and deep cortical activity in the primate brain using transcranial focused ultrasound stimulation. Folloni, D., et al. Neuron 101(6): 1109-1116. (2019)
- Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behaviour. Fomenko, A., et al. eLife 9. (2020)
- The macaque anterior cingulate cortex translates counterfactual choice value into actual behavioural change. Fouragnan, E.F., et al. Nature Neuroscience 22: 797-808. (2019)
- The brain electrophysiological recording and stimulation (BEST) toolbox. Hassan, U., Pillen, S., Zrenner, C. and Bergmann, T.O. Brain Stimulation 15(1): 109-115. (2022)
- A basal forebrain-cingulate circuit in macaques decides it is time to act. Khalighinejad, N., et al. Neuron 105(2): 370-384. (2020)
- Non-invasive transmission of sensorimotor information in humans using an EEG/focused ultrasound brain-to-brain interface. Lee, W., et al. PLoS ONE 12(6). (2017)
- Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Lee, W., Kim, H. and Jung, Y. et al. Scientific Reports 5(8743. (2015)
- Neuromodulation with single-element transcranial focused ultrasound in human thalamus. Legon, W., Ai, L., Bansal, P. and Mueller, J.K. Human Brain Mapping 39(5): 1995-2006. (2018a)
- Transcranial focused ultrasound neuromodulation of the human primary motor cortex. Legon, W., Bansal, P. and Tyshynsky, R. et al. Scientific Reports 8(10007). (2018b)
- Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Legon, W., et al. Nature Neuroscience 17: 322-329. (2014)
- Transcranial focused ultrasound modulated intrinsic and evoked EEG dynamics. Mueller, J., Legon, W. and Opitz, A. et al. Brain Stimulation 7(6): 900-908. (2014)
- MRI monitoring of temperature and displacement for transcranial focus ultrasound applications. Ozenne, V., et al. NeuroImage 204. (2020)
- Transcranial focused ultrasound generates skull-conducted shear waves: computational model and implications for neuromodulation. Salahshoor, H., Shapiro, M.G. and Ortiz, M. Applied Physics Letters 117(3). (2020)
- Offline impact of transcranial focused ultrasound on cortical activation in primates. Verhagen, L., et al. eLife 8. (2019)
- Transcranial ultrasonic stimulation modulates single-neuron discharge in macaques performing an antisaccade task. Wattiez, N., et al. Brain Stimulation 10(6): 1024-1031. (2017)
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