Controlled ultrasonic interventions through the human skull
Matthew G. Wilson, Thomas S. Riis, Jan Kubanek
Frontiers in Human Neuroscience 2024 · 10.3389/fnhum.2024.1412921
Abstract
Transcranial focused ultrasound enables precise and non-invasive manipulations of deep brain circuits in humans, promising to provide safe and effective treatments of various neurological and mental health conditions. Ultrasound focused to deep brain targets can be used to modulate neural activity directly or localize the release of psychoactive drugs. However, these applications have been impeded by a key barrier-the human skull, which attenuates ultrasound strongly and unpredictably. To address this issue, we have developed an ultrasound-based approach that directly measures and compensates for the ultrasound attenuation by the skull. No additional skull imaging, simulations, assumptions, or free parameters are necessary; the method measures the attenuation directly by emitting a pulse of ultrasound from an array on one side of the head and measuring with an array on the opposite side. Here, we apply this emerging method to two primary future uses-neuromodulation and local drug release. Specifically, we show that the correction enables effective stimulation of peripheral nerves and effective release of propofol from nanoparticle carriers through an ex vivo human skull. Neither application was effective without the correction. Moreover, the effects show the expected dose-response relationship and targeting specificity. This article highlights the need for precise control of ultrasound intensity within the skull and provides a direct and practical approach for addressing this lingering barrier.
Abstract via europepmc.
Exposures
Exposure 1: Nerve stimulation of the human thumb through an ex-vivo skull
Target: peripheral nerve — “peripheral nerves within the human thumb”
Device: not reported · two spherically focused 126-element arrays driven by Vantage256 (Verasonics) ✓
| Waveform | continuous | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | not applicable | |
| Pulse repetition frequency (Hz) | not applicable | |
| Duty cycle (%) | not applicable | |
| Sonication duration (s) | 0.3 | ✓✓✓ |
| Free-field pressure (kPa) | 1,300, 1,550, 1,800swept | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | 730, 1,840, 1,950swept | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
A single 300 ms stimulus delivered every 8-12 s in randomised order, 10 repetitions of each of eight stimulus types (correction method x pressure level, plus sham) per subject, 80 trials per subject.
Exposure 2: Propofol release from nanoparticles in vials inside an ex-vivo skull
Target: other — “vials of nanoparticle solution at a central location within the skull”
Device: not reported · two spherically focused 126-element arrays driven by Vantage256 (Verasonics) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 100 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 1 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 10% | ⚑ |
| Sonication duration (s) | 60 | ✓✓✓ |
| Free-field pressure (kPa) | 1,300, 1,550, 1,800swept | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | 730, 1,840, 1,950swept | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
The ultrasound was pulsed for 100 ms every 1 s for 60 s; n = 10 vials per condition, conditions randomly interleaved.
Flags from extraction
exposures[0].free_field.pressure_kpa— Intended peak pressure levels 1.3, 1.55 and 1.8 MPa (nerve) and 1.2, 1.5 and 1.8 MPa (drug release) were swept; only the highest, 1.8 MPa in free-field, is recorded. Pressures with skull and correction (0.73, 1.84, 1.95 MPa) not placed in any domain.exposures[1].free_field.pressure_kpa— Sweep of 1.2, 1.5, 1.8 MPa; only 1.8 MPa recorded.exposures[1].timing.duty_cycle_pct— Duty cycle not stated; 100 ms every 1 s not converted.exposures[0].device.family— Array device is described as previously published; maker not named; Verasonics is driving electronics only.model_system— Only one ex-vivo skull; nerve stimulation was in living human thumbs placed inside the skull; drug release used vials of nanoparticle solution.blinding— A blinded experimenter recorded percepts; subjects' blinding to condition inferred from earmuffs and closed eyes, not stated as single-blind.sham_type— Sham steered the focus 10 mm below the target; a no-ultrasound vial control was also used for drug release.