Transcranial focused ultrasound induces source localizable cortical activation in resting state humans when applied concurrently with transcranial electric stimulation
Joshua Kosnoff, Colton Gonsisko, Kai Yu, Joseph Zhang, Yidan Ding, Yisha Zhang, Bin He
Nature Communications 2026, 17 · 10.1038/s41467-026-69853-8
Abstract
The effects of transcranial focused ultrasound (tFUS) on the human brain are poorly understood. Currently, the field is at odds with whether tFUS is subthreshold modulating the brain's excitability towards other stimuli, producing suprathreshold neural stimulation on its own, or if it even has a spatially specific non-auditory induced effect. Herein, we investigated the ability of tFUS, transcranial direct current stimulation (tDCS), and a combination of the two (transcranial electro-acoustic stimulation; tEAS) to evoke cortical target-location specific activity in 27 resting state humans with whole-brain electroencephalography recordings. In none of the exogenous event-related potentials did tFUS or tDCS result in location-specific activations. However, the co-modulatory combination of tEAS provided evidence that tFUS has a location-specific subthreshold modulatory effect. We propose a minimally modified Hodgkin-Huxley model that explains our results and provides a unifying framework for the field-wide observed effects (or lack thereof) of tFUS.
Abstract via europepmc.
Exposures
Exposure 1: tFUS to left primary motor cortex (itFUS/etFUS and tEAS conditions; main study plus follow-up parameter sweeps)
Target: primary motor cortex — “left motor cortex”
Device: Blatek · Blatek Industries Inc. ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | not reported | ⚑ |
| Pulse repetition frequency (Hz) | 30, 3,000, 40, 1,500swept | ✓✓✓⚑ |
| Duty cycle (%) | 0.6, 10, 30, 60swept | ✓✓✓⚑ |
| Sonication duration (s) | 0.5, 0.1swept | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | 231, 250, 300swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | 0.16, 1.24swept | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.0486, 0.372swept | ✓✓✓ |
| Pressure, domain unspecified (kPa) | 980 | ✓✓✓⚑ |
500 kHz tFUS pulsed every two seconds (up to 20% random jitter) for 200 trials per condition; PRF of 3 kHz was defined as excitatory and 30 Hz as inhibitory, with cycles-per-pulse/pulse-number varied to hold sonication duration (500 ms) and duty cycle (30%) constant in the main study. A follow-up parameter search in 10 of the 22 original subjects also tested 1500 and 40 Hz PRFs at 30% DC, and 10% and 60% DC (later replaced by 0.6% DC after the first four subjects found 60% DC uncomfortable) at 30 and 3000 Hz PRF. A separate follow-up in 11 subjects also tested an inaudible 30 kHz PRF, and another follow-up in 11 subjects normalized in situ pressure to 300 kPa with sonication duration reduced to 100 ms. A further six-subject follow-up tested a smoothed, inaudible waveform (pulse duration 3.25 ms, 1 ms Tukey ramp, 250 Hz PRF) instead of the rectangular pulses used elsewhere.
Exposure 2: tFUS spatial control to right prefrontal cortex (etDCS/itDCS control conditions, and additional 3 kHz tFUS control)
Target: prefrontal cortex — “right prefrontal cortex (RH PFC)”
Device: Blatek · Blatek Industries Inc. ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | not reportedimplied by duty cycle ÷ PRF: 0.1 ms (not stated by the paper) | |
| Pulse repetition frequency (Hz) | 3,000 | ✓✓✓ |
| Duty cycle (%) | 30 | ✓✓✓ |
| Sonication duration (s) | 0.5 | ✓✓✓ |
| 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 |
Off-target spatial control condition using the same 500 kHz transducer aimed at the right prefrontal cortex (between electrodes AF4, AF8, F4, F6) instead of left M1, with excitatory (3 kHz PRF) parameters; duty cycle and sonication duration held the same as the on-target conditions.
Flags from extraction
n_subjects— Abstract and Ethics section state 27 total subjects, but cohort breakdown (22, 11, 11, 6, 8, with overlap) does not resolve to a single unambiguous total; 27 is used as stated.n_sessions_per_subject— Number of sessions per subject not stated as a single figure; design includes a main session plus several distinct follow-up call-back studies with partially overlapping subjects.auditory_control— Paper extensively discusses auditory confounds (Granger causality, ERP topology) as a finding but does not describe implementing any masking/deafening control for the main experiment; classified as not_reported rather than none.exposures[0].unspecified_domain.pressure_kpa— 0.98 MPa is described as normalized 'with respect to the energy delivered on the scalp', which is neither clearly free-field/water nor in-situ/brain; placed in unspecified_domain.exposures[0].in_situ.pressure_kpa— A third in-situ pressure normalization target (250 kPa) is mentioned in the same Methods paragraph as 300 kPa but not in a single quotable sentence with 231/300 kPa, so it is omitted from the list and only described in protocol_description.exposures[0].timing.pulse_repetition_frequency_hz— An additional inaudible 30 kHz PRF follow-up is described in the main text but only in a sentence that does not also contain the other swept PRF values; included in protocol_description only.exposures[0].timing.duty_cycle_pct— A 0.6% duty cycle was also tested (replacing 60% DC after subject discomfort) but is reported in a separate sentence from the other duty-cycle values; included in protocol_description only.exposures[0].timing.pulse_duration_ms— Pulse duration is not stated in ms for the rectangular-pulse conditions (cycles-per-pulse varied by PRF to hold duty cycle/sonication duration constant); only the separate smoothed-waveform follow-up study reports an explicit pulse duration (3.25 ms), described in protocol_description.sham_type— There is no acoustic sham for tFUS itself; the only control is an active spatial control at a different site (RH PFC) for the tDCS conditions.