Neurodegeneration Associated with Repeated High-Frequency Transcranial Focused Ultrasound
AP Brna, O Favorov, T Challener, AO Biliroglu, FY Yamaner, RE Kemal, M Annayev, O Oralkan, D Eidum, SB Simons, MP Weisend, PM Connolly
2025 · 10.1101/2025.09.23.674044
Abstract
Transcranial Focused Ultrasound (tFUS) is a popular tool for non-invasive neuromodulation which prior testing paradigms have suggested is benign. However, emerging use cases such as clinical therapies and brain-machine interfaces will likely require repeated or long-duration exposures with novel combinations of stimulus parameters (e.g., frequency, focal volume), and the safety of these conditions has not yet been rigorously validated. Therefore, as an initial study we delivered 1.8 MHz tFUS stimulation to the cortex of 4 non-human primates in 4 sessions each of approximately 90 min over 2 weeks. Motor skills were measured daily with a food pellet picking task. Animals were euthanized and the brain sections were processed for histological markers of neurodegeneration (Fluoro-Jade C). While the animals did not show disruption on the behavioral task, there was clear evidence of neurodegeneration in regions associated with short, intermediate, and extended-duration stimulation, but not with unstimulated control tissues in deeper brain areas. Additional neurodegeneration was observed at locations distant from but functionally connected to stimulated regions, consistent with retrograde damage propagated from neuron processes. We discuss alternative causes for the neurodegeneration, and we recommend the use of additional animal studies to understand this phenomenon, especially for novel stimulation paradigms or parameters and applications where extended or repeated exposures are planned.
Abstract via europepmc.
Exposures
Exposure 1: 1.8 MHz tFUS to sensorimotor cortex (extended, intermediate and short-duration sites)
Target: sensorimotor cortex, motor cortex — “sensorimotor region of one hemisphere”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,800 | ✓✓✓ |
| Pulse duration (ms) | not reported | ⚑ |
| Pulse repetition frequency (Hz) | not reported | |
| Duty cycle (%) | 50 | ✓✓✓⚑ |
| Sonication duration (s) | 0.15 | ✓✓✓⚑ |
| Free-field pressure (kPa) | 2,300 | ✓✓✓⚑ |
|---|---|---|
| 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) | not reported | |
| In-situ Isppa (W/cm²) | 18.2, 65.4swept | ✓✓✓⚑ |
| In-situ Ispta (W/cm²) | 9.1, 32.7swept | ✓✓✓⚑ |
Pulse train repeats of 150 ms pulse trains with a 10 s inter-stimulus interval for up to 90 min per session (about 2 h of stimulation including setup), 4 sessions over 2 weeks. Each site type (extended, intermediate, short) received a different cumulative exposure time; short-duration sites were stimulated in sequence.
Flags from extraction
exposures[0].in_situ.isppa_w_cm2— Derated ISPPA from Fullwave simulation, range across sites and animals read from Table 1 (min 18.2, max 65.4); caption says 'derated' so recorded as simulation.exposures[0].in_situ.ispta_w_cm2— Table gives ISPTA of the pulse train (ISPPA x train duty cycle), not a conventional whole-sonication Ispta; range from Table 1.exposures[0].timing.duty_cycle_pct— 50 % is the pulse-train duty cycle (DC_Train) per Table 1 caption; pulse duration and PRF are shown only in Figure 1e, not in text.exposures[0].timing.pulse_duration_ms— Pulse duration and PRF only in Figure 1e, not stated in text.exposures[0].timing.sonication_duration_s— 150 ms is the pulse train duration; total exposure time per site is in Table 1.exposures[0].free_field.pressure_kpa— 2.3 MPa measured free field for a short-duration site on NHP-B excised skull setup; text says free-field and through-skull profiles were comparable.exposures[0].device.family— Paper describes a 1024-element CMUT phased array with custom ASIC but does not name a manufacturer or say who built it in this text.exposures[0].target.terms— Targets described as sensorimotor region, extended site anterior to central sulcus in motor cortex.