Parameter optimisation for mitigating somatosensory confounds during transcranial ultrasonic stimulation
Benjamin R. Kop, Linda de Jong, Butts Pauly Kim, Hanneke E.M. den Ouden, Lennart Verhagen
Brain Stimulation 2025, 18, 1224-1236 · 10.1016/j.brs.2025.06.009
Abstract
Background Transcranial ultrasonic stimulation (TUS) redefines what is possible with non-invasive neuromodulation by offering unparalleled spatial precision and flexible targeting capabilities. However, peripheral confounds pose a significant challenge to reliably implementing this technology. While auditory confounds during TUS have been studied extensively, the somatosensory confound has been overlooked thus far. It will become increasingly vital to quantify and manage this confound as the field shifts towards higher doses, more compact stimulation devices, and more frequent stimulation through the temples where co-stimulation is more pronounced. Methods Here, we provide a systematic characterisation of somatosensory co-stimulation during TUS. We also identify the conditions under which this confound can be mitigated most effectively by mapping the confound-parameter space. Specifically, we investigate dose-response effects, pulse shaping characteristics, and transducer-specific parameters. Results We demonstrate that somatosensory confounds can be mitigated by avoiding near-field intensity peaks in the scalp, spreading energy across a greater area of the scalp, ramping the pulse envelope, and delivering equivalent doses via longer, lower-intensity pulses rather than shorter, higher-intensity pulses. Additionally, higher pulse repetition frequencies and fundamental frequencies reduce somatosensory effects. Through our systematic mapping of the parameter space, we also find preliminary evidence that particle displacement (strain) may be a primary biophysical driving force behind peripheral somatosensory co-stimulation. Conclusion This study provides actionable strategies to minimise somatosensory confounds, which will support the thorough experimental control required to unlock the full potential of TUS for scientific research and clinical interventions.
Abstract via europepmc.
Exposures
Exposure 1: Standard 250 kHz protocol at temporal-lobe white matter, with dose/dose-modality, ramping, PRF, aperture, near-field-peak and temporal-summation manipulations
Target: white matter — “white matter of the temporal lobe”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · 250-2CH (CTX250-014); 250-4CH (CTX250-026) used for the aperture-area comparison ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 50, 100, 150, 200swept | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5, 10, 50, 100, 200, 500, 1,000swept | ✓✓✓ |
| Duty cycle (%) | 50 | ✓✓✓⚑ |
| Sonication duration (s) | 1, 10swept | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 19.72, 13.06, 6.5, 13.1, 19.6, 26.1, 5.23swept | ✓✓✓⚑ |
Standard protocol: square-wave PRF 5 Hz, PRI 200 ms, PD 100 ms, DC 50%, PTD 1 s, ISPPA 19.72 W/cm2 (ISPPA,SCALP 13.06 W/cm2), inter-trial interval ~10 s. Around this standard, the study independently manipulated: dose (3.3/6.5/9.8/13.1 J/cm2) via either ISPPA.SCALP (6.5/13.1/19.6/26.1 W/cm2, PD fixed 100 ms) or PD (50/100/150/200 ms, ISPPA.SCALP fixed 13.1 W/cm2); ramping (tapered cosine amplitude-modulation durations of 1, 10, 50 ms vs square wave); PRF (5/10/50/100/200/500/1000 Hz, each with full Tukey ramping); transducer aperture area (15.90 cm2 250-2CH vs 33.18 cm2 250-4CH, equal integrated total scalp intensity); near-field peak amplitude via focal depth (35.7/38.3/40.3(standard)/42.1/44.1 mm, corresponding to manufacturer-reported near-field scalp intensities of 5.3/9.4/13.8/17.9/22.3 W/cm2); and temporal summation (interspersed vs sequential trials, trial blocks, and an extended 10-s PTD at ISPPA.SCALP = 5.23 W/cm2).
Exposure 2: 500 kHz dose-response protocol at temporal-lobe white matter
Target: white matter — “white matter of the temporal lobe”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · 500-2CH (CTX500-006) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 100 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 1 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 18.5, 30.8, 43.1swept | ✓✓✓ |
The dose-response relationship at 500 kHz was mapped similarly to 250 kHz, by manipulating ISPPA.SCALP (18.5/30.8/43.1 W/cm2); the paper does not restate PD/PRF/duty-cycle/PTD values specifically for the 500 kHz condition (Supplementary Fig. 8).
Flags from extraction
n_subjects— 25 participants completed the study, but one was later excluded for psychological distress and their data was not analysed (analysed n=24); enrolled/completed n=25 is given per instructions, analysed n differs.exposures[0].unspecified_domain.isppa_w_cm2— List combines intensity values from several sentences (standard protocol ISPPA=19.72 and ISPPA,SCALP=13.06 W/cm2; dose-modality sweep 6.5/13.1/19.6/26.1 W/cm2; extended-duration test 5.23 W/cm2); only the dose-modality sentence is quoted directly. The paper never labels these as 'free field' or 'in situ' (brain) values; ISPPA,SCALP is explicitly a near-field scalp measurement, distinct from a brain/target value, so all are placed in unspecified_domain rather than free_field/in_situ.exposures[0].timing.duty_cycle_pct— 50% duty cycle is stated only for the standard protocol; the paper does not restate duty cycle for the PD sweep (50/100/150/200 ms) or PRF sweep (5-1000 Hz) conditions, where it may differ.exposures[0]— The 250 kHz exposure also included near-field-peak (focal depth 35.7-44.1 mm; manufacturer scalp intensities 5.3-22.3 W/cm2) and transducer-aperture-area (15.90 vs 33.18 cm2) manipulations not captured as separate numeric list entries; see protocol_description.exposures[1].timing— Timing parameters (PD, PRF, duty cycle, PTD) are not explicitly restated for the 500 kHz dose-response experiment; only the ISPPA.SCALP sweep (18.5/30.8/43.1 W/cm2) is given in the main text.