Simulation guided parameter optimization for tFUS targeting the left DLPFC: short term safety and parameter specific responses in humans
Jingxuan Wang, Hujun Wang, Yingpeng Wang, Congxiao Wang, Chenye Qiao, Ning Li, Yingqi Li, Shuyan Qie
2026 · 10.2139/ssrn.7076166
Abstract
Objective: Neurophysiological responses to transcranial focused ultrasound stimulation (tFUS) may be jointly shaped by multiple parameters, including center frequency, duty cycle and acoustic field distribution. This study aimed to establish a tFUS parameter screening framework based on coupled acoustic and thermal simulations and, in healthy middle aged and older adults, to conduct a preliminary within subject randomized crossover investigation of short term electrophysiological, hemodynamic, cognitive, safety and tolerability responses after stimulation of the left dorsolateral prefrontal cortex (DLPFC) with different parameter combinations.Methods: We first performed acoustic and thermal numerical simulations in BabelBrain using a standard head model and left DLPFC target across ranges of center frequency (FF), duty cycle (DC) and pulse parameters. Feasible and safe parameters were screened according to the mechanical index, spatial peak pulse average intensity, spatial peak temporal average intensity and temperature rise thresholds. Parameter combinations were then selected by considering transcranial transmission efficiency, focal volume and focusing characteristics. The human experiment used a within subject randomized crossover design and enrolled 30 healthy middle aged and older adults. The primary outcome was the pre to post stimulation change in absolute alpha band power over the left frontal EEG region. Other EEG frequency bands, functional near infrared spectroscopy (fNIRS), behavioral performance and safety measures were assessed as secondary and exploratory outcomes.Results: Simulations showed that center frequency mainly affected transcranial propagation efficiency and focal morphology, whereas duty cycle primarily affected time averaged energy delivery and temperature rise. All four selected protocols met the predefined mechanical and thermal safety thresholds. In the human experiment, all participants completed the study procedures, and no stimulation related serious adverse events occurred. EEG analyses showed parameter dependent changes in band specific power. The 500 kHz/20% DC protocol produced the most prominent change in absolute alpha band power over the left posterior frontal region, which remained statistically significant after FDR correction. Whole brain topographic results suggested spatially structured positive changes in the alpha band and decreasing trends in the delta band. fNIRS and behavioral results showed that the four parameter combinations produced distinct spatial patterns of HbO change and task performance trends during the Corsi and Go/NoGo tasks. Exploratory correlation analyses showed moderate uncorrected associations between HbO changes in some ROIs and behavioral changes in the Corsi task, but these associations did not remain significant after FDR correction.Conclusions: These preliminary findings suggest that acoustic thermal simulation-based parameter screening can provide quantitative guidance for human exploratory studies of DLPFC targeted tFUS. The 500 kHz/20% DC protocol showed a relatively prominent exploratory signal in the left frontal alpha response. However, because this was a single session active parameter comparison study in healthy middle aged and older adults and did not include a sham stimulation control, the present data cannot define optimal therapeutic parameters or support definitive efficacy inferences. These findings require further validation in larger, strictly doub
Abstract via crossref.
Exposures
Exposure 1: tFUS to left DLPFC, 500 kHz protocols (20% and 50% duty cycle)
Target: dorsolateral prefrontal cortex — “left dorsolateral prefrontal cortex (DLPFC)”
Device: other named manufacturer · Jiangsu Zhongke Yinbian Medical Technology Co., Ltd. · ZK JLCS 8601 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | not reported | |
| Pulse repetition frequency (Hz) | 50 | ✓✓✓ |
| Duty cycle (%) | 50, 20swept | ✓✓✓ |
| Sonication duration (s) | 1,800 | ✓✓✓ |
| Free-field pressure (kPa) | 480 | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | 3 | ✓✓✓⚑ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | ⚑ |
| In-situ Ispta (W/cm²) | not reported |
Each of 30 participants received all four active parameter protocols (500 kHz and 800 kHz, each at 20% and 50% duty cycle) across four visits in a within-subject randomized crossover design (Williams balanced Latin square), with a washout interval of more than 24 h between protocols. No sham stimulation control was included; the human component was designed for active parameter comparison and short-term safety/feasibility assessment.
Consistency checks: intensity pressure inconsistent free field.
Exposure 2: tFUS to left DLPFC, 800 kHz protocols (20% and 50% duty cycle)
Target: dorsolateral prefrontal cortex — “left dorsolateral prefrontal cortex (DLPFC)”
Device: other named manufacturer · Jiangsu Zhongke Yinbian Medical Technology Co., Ltd. · ZK JLCS 8601 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 800 | ✓✓✓ |
| Pulse duration (ms) | not reported | |
| Pulse repetition frequency (Hz) | 50 | ✓✓✓ |
| Duty cycle (%) | 50, 20swept | ✓✓✓ |
| Sonication duration (s) | 1,800 | ✓✓✓ |
| Free-field pressure (kPa) | 1,530 | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | 3 | ✓✓✓ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Each of 30 participants received all four active parameter protocols (500 kHz and 800 kHz, each at 20% and 50% duty cycle) across four visits in a within-subject randomized crossover design (Williams balanced Latin square), with a washout interval of more than 24 h between protocols. No sham stimulation control was included; the human component was designed for active parameter comparison and short-term safety/feasibility assessment.
Consistency checks: intensity pressure inconsistent free field.
Flags from extraction
exposures[0].free_field.isppa_w_cm2— Paper states 'free field acoustic intensity was set to 3 W/cm2' without specifying whether this is spatial-peak pulse-average or temporal-average intensity; recorded as isppa_w_cm2 by convention for a device intensity setting.exposures[0].in_situ.isppa_w_cm2— 'Nominal intensity at the actual focus was below 0.3 W/cm2' is an upper-bound statement, not an exact measured value, and the paper does not state whether it was derived by simulation or derating; recorded as 0.3 with method set to derating as a best fit.exposures[0].free_field.pressure_kpa— Table 3's 'Intensity (W/cm2)' column shows '3' only for the 500 kHz protocols and appears blank for the 800 kHz protocols, though the text states a single free-field intensity (3 W/cm2) applies to all four protocols; used the text statement.exposures— Study is a 2x2 sweep of center frequency (500/800 kHz) and duty cycle (20%/50%) at one target (left DLPFC); split into one exposure per frequency with duty_cycle_pct as a list, per the one-exposure-per-target-x-frequency rule.auditory_control— Paper does not explicitly state 'no auditory control was used' in methods, but lists inability to exclude auditory or somatosensory co-stimulation as a limitation because no sham was included; inferred as none.direction_of_effect— Only one of four parameter combinations reached significance after FDR correction for the primary EEG outcome; other outcomes (fNIRS, behaviour) were largely non-significant after correction.