Transcranial Ultrasound Studies, Part 2

The Lit Review Grows

I’ve collected even more studies (though still, unfortunately, not all of them) on what transcranial ultrasound stimulation does in animals and humans.

Link to the spreadsheet is here.

Totals and Averages

• Total studies: 71

  • Human: 27

  • Macaque: 8

  • Pig: 1

  • Sheep: 5

  • Mouse: 19

  • Rat: 13

• Brain regions:

  • thalamus: 11

  • motor cortex: 8

  • somatosensory cortex: 6

  • hippocampus: 6

  • prefrontal cortex: 5

  • visual cortex: 3

  • other: 9

Mean spatial peak-pulse average intensity: 11 W/cm^2 +/- 14

Mean acoustic frequency: 750 kHz +/- 1000

Mean pulse repetition frequency: 1.4 kHz +/- 5

Mean duty cycle: 31% +/- 23%

Effects: Excitatory or Inhibitory?

In almost every study (19/21) that directly measured the effect of transcranial ultrasound on the neural activity in the targeted brain region, the effect of ultrasound was to stimulate activity.

Whether measured by fMRI BOLD signal, PET glucose uptake, direct electrode measurement, or cFos expression (a gene that serves as a measure of neural activation), in humans, monkeys, mice, and rats, in various regions of the brain, low-intensity focused transcranial ultrasound has a stimulating effect on neural activity in the targeted region.

The two exceptions were a study on coma patients, where fMRI showed no stimulating effect, and a rat study examining a combination of ultra-low-intensity ultrasound and microbubbles for opening the blood brain barrier, where it had an inhibitory effect. But it’s easy to imagine that both of these are nonrepresentative situations which don’t cast doubt on how ultrasound alone works in non-comatose animals.

In all the other studies, transcranial ultrasound increases the amplitude and frequency of firing at its target region, as well as other correlates like blood flow, glucose uptake, and cFos expression.

This is consistent with a mechanism in which low-intensity focused ultrasound alters ion channels and thus a neuron’s propensity to fire.

In particular, Yu 2021¹ found that ultrasound activated only the excitatory but not the inhibitory neurons in the somatosensory cortex; and Zu 2023² found that when you knock out the Piezo1 gene, a mechanosensitive ion channel protein, most of the effect of ultrasound goes away.

Once again, this is pretty consistent with a mechanism whereby mechanical pressure from ultrasound does something to ion channels to make (maybe a subpopulation of) neurons fire more.

There’s also a skeptical view that ultrasound “works” by simply heating the tissue — but the one paper that found that mere laser heating behaved exactly the same as ultrasound stimulation³ also used an unusually high, 3.2 MHz, frequency of ultrasound, higher than in any other study in my collection. This is still consistent with a model in which both heating and mechanical-pressure mechanisms exist, but the heating effect predominates at high intensities and the pressure effect predominates at low ones.

In terms of local acute effects, it looks to me like low-intensity transcranial focused ultrasound at <2MHz frequencies is pretty consistently excitatory.

In terms of global effects, the “direction” is mixed. When you look at EEG measurements of how “responsive” brain electric fields are to sensory or motor stimuli (the “evoked potential”) some studies find that ultrasound increases responsiveness and others find that ultrasound decreases it, even when looking at the same brain regions.

Likewise, ultrasound stimulation of the motor cortex can make it more or less responsive to stimulation by other methodologies like magnetic stimulation.

Some studies⁴⁵⁶ found that ultrasound protocols with high duty cycles (mostly on) increase these measures of responsiveness, while low duty cycles (mostly off) decrease them. Does this generalize? We Just Don’t Know.

Functional Effects: What Does It Do?

So far, mostly, transcranial ultrasound does stuff we don’t care much about from a clinical perspective.

It can make muscles twitch, make subjects feel tingling or see flashes of light, that sort of thing.

Some stuff is more suggestive:

It can make animals come out of anaesthesia faster; sometimes it improves performance on animal and human cognitive tests (though not in Alzheimer’s patients) and sometimes it improves mood or depression symptoms (though not in every study). It can sharpen sensory perceptions and reduce reaction time.

Also, it locally opens the blood-brain barrier, activates microglia, and increases solute clearance into the lymphatic system. This is less interesting from a neuromodulation perspective, but it might be useful for neurodegenerative or brain-injury applications. (Also, it’s a pointer to potential risks of neuromodulatory ultrasound — you have a blood-brain barrier for a reason!)

But the bottom line is, even 71 studies in to a very active field, the question of “what can you do with transcranial ultrasound?” is very much an open one. Most of the attention has gone into “can you even aim it where you want and get a bona fide targeted neuromodulation effect?” The cool shit is yet to be discovered.

(Not that some people aren’t trying. Jay Sanguinetti at the University of Arizona has collaborated with meditation teacher Shinzen Young to investigate the neuroscience of meditative states, considers human neuroenhancement a research interest, and has consistently been exploring the “big questions” in human ultrasound studies — can it shift people from “avoid” to “approach” motivation? Reduce learned helplessness? Reduce depressive rumination? Big If True, as they say.)

1. Yu, Kai, et al. "Intrinsic functional neuron-type selectivity of transcranial focused ultrasound neuromodulation." Nature communications 12.1 (2021): 2519.

2. Zhu, Jiejun, et al. "The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation." Proceedings of the National Academy of Sciences 120.18 (2023): e2300291120.

3. Darrow, David P., et al. "Reversible neuroinhibition by focused ultrasound is mediated by a thermal mechanism." Brain stimulation 12.6 (2019): 1439-1447.

4. Zhang, Tingting, et al. "Excitatory‐inhibitory modulation of transcranial focus ultrasound stimulation on human motor cortex." CNS Neuroscience & Therapeutics (2023).

5. Yoon, Kyungho, et al. "Effects of sonication parameters on transcranial focused ultrasound brain stimulation in an ovine model." PloS one 14.10 (2019): e0224311.

6. Kim, Hyun-Chul, et al. "Transcranial focused ultrasound modulates cortical and thalamic motor activity in awake sheep." Scientific reports 11.1 (2021): 19274.