This work demonstrates that TUS can indeed be felt, provides a roadmap for managing participant burden, and supports proper experimental blinding to enhance the validity of TUS research. Thank you to my collaborators @lennartverhagen.bsky.social, Hanneke den Ouden, Kim Butts Pauly, & Linda de Jong!

Interestingly, our results also provide preliminary evidence that particle displacement is a primary biophysical driving force underlying somatosensory co-stimulation. In the future, we may be able to leverage such insights to maximise CNS neuromodulatory efficacy while minimizing confounds.

While considering influence on CNS neuromodulation (!!), we can:

- Eliminate near-field intensity peaks in the scalp
- Use larger aperture areas
- Apply ramping
- Deliver equivalent doses via longer, lower intensity pulses
- Apply higher PRFs (≥200 Hz)
- Apply higher f0 (e.g., 500 vs 250 kHz)

How can we reduce these somatosensory confounds without compromising neuromodulation in the brain by reducing dose? Our systematic parameter mapping reveals several possible strategies:

All participants in our study reported feeling something during TUS. Tactile sensations like 'buzzing' and 'prickling' emerged at lower doses, with thermal and painful sensations emerging as dose increased. This poses a real challenge for blinding.

We applied TUS through the temples and measured participants' somatosensory experience at the stimulation site (VAS/threshold). We tested several stimulation protocols across three different transducers to identify avenues for confound mitigation.

This work demonstrates that TUS can indeed be felt, provides a roadmap for managing participant burden, and supports proper experimental blinding to enhance the validity of TUS research. Thank you to my collaborators @lennartverhagen.bsky.social, Hanneke den Ouden, Kim Butts Pauly, & Linda de Jong!

Interestingly, our results also provide preliminary evidence that particle displacement is a primary biophysical driving force underlying somatosensory co-stimulation. In the future, we may be able to leverage such insights to maximise CNS neuromodulatory efficacy while minimizing confounds.

While considering influence on CNS neuromodulation (!!), we can:
- Eliminate near-field intensity peaks in the scalp
- Use larger aperture areas
- Apply ramping
- Deliver equivalent doses via longer, lower intensity pulses
- Apply higher PRFs (≥200 Hz)
- Apply higher f0 (e.g., 500 vs 250 kHz)

How can we reduce these somatosensory confounds without compromising neuromodulation in the brain by reducing dose? Our systematic parameter mapping reveals several possible strategies:

All participants in our study reported feeling something during TUS. Tactile sensations like 'buzzing' and 'prickling' emerged at lower doses, with thermal and painful sensations emerging as dose increased. This poses a real challenge for blinding.

We applied TUS through the temples and measured participants' somatosensory experience at the stimulation site (VAS/threshold). We tested several stimulation protocols across three different transducers to identify avenues for confound mitigation.

We speculate on why prior findings don’t replicate in our manuscript, but one thing is clear: double-blinding, TUS (& TMS) neuronavigation, and acoustic simulations are key to supporting the replicability required for TUS to truly make waves!

For those of you now concerned about using this protocol, don't worry! There are still multiple convincing studies using 5Hz-rTUS/tbTUS with promising results, so there's no need to abandon it. Instead, let's focus our efforts on reproducibility in this quickly expanding field!

This raises big questions:
How were such consistent excitatory effects found in prior work with variable hotspot-based targeting? Particularly considering that another independent study using 5Hz-rTUS with confirmed structural targeting reported opposite (inhibitory) effects! 🤔

Importantly, when M1 was effectively targeted, we still didn't find evidence for offline excitatory effects!

We replicated the same TMS hotspot-based targeting approach for TUS as prior work, but by introducing post-hoc simulations we showed that this method can lead to unacceptable M1 targeting variability as compared to structurally/functionally informed targeting.

The strong & prolonged excitatory effects of 5Hz-rTUS (tbTUS) reported several times by one research group didn't replicate over APB, FDI, or ADM muscles. TUS targeting might contribute to this variability, though it cannot explain such a large discrepancy in results.

In this pre-registered study, we precisely replicated prior methodology, but added some key improvements:
- double-blinding
- TMS neuronavigation
- post-hoc acoustic simulations

TMS and EMG were used to capture intracortical and corticospinal excitability (SICI, ICF, & MEP).