A pilot safety and tolerability study of scanning ultrasound as a neuromodulation therapy in Alzheimer’s disease
Peter J Nestor, Matthew Pelekanos, Gerhard Leinenga, Jae Song, Wendy Lee, Gina Richter-Stretton, Caitlin McElligott, Amir Fazlollahi, Jason B Mattingley, Anthony Harris, Henry Beale, Jennie Roberts, Rachel de las Heras, Jürgen Götz
Brain Communications 2025 · 10.1093/braincomms/fcaf445
Abstract
Clearing amyloid-β pathology in Alzheimer's disease (AD) has been considered a prerequisite for restoring cognitive functions. Intriguingly, by application of a modality of scanning ultrasound (SUS) to mice that does not remove amyloid-β, we previously achieved significant cognitive improvements. This prompted us to explore SUS as a non-invasive brain stimulation strategy in an open-label safety trial in AD. We conducted a human pilot study in 12 participants with AD with the primary objective of determining feasibility, safety and tolerability. Exploratory secondary end-points were cognitive and behavioural measures, resting-state EEG and functional MRI. A portable device termed UltraThera Pilot was built under medical device standard guidelines, integrating a Brainsight image-guided neuronavigation system. A single-element 286-kHz transducer was programmed to deliver non-derated ultrasound doses of 2.6, 1.95 or 1.3 MPa. With four treatment sessions spaced fortnightly, four participants received 30 sonications per session (precuneus, ∼30 cm 3 brain tissue) and the remaining 8 received 100 sonications per session (bilateral precuneus and temporo-parietal association cortex, ∼100 cm 3 ). Safety monitoring, EEG, MRI, cognitive and neuropsychiatric evaluations were performed. The treatment was fast, safe and well-tolerated at the 1.95 MPa dose. MRI showed no changes, whereas changes were observed in aperiodic EEG content. Cognitive performance did not change but statistically significant improvements in behavioural and psychological symptoms were found using the Neuropsychiatric Inventory test. In conclusion, this SUS safety trial met its primary and secondary end-points in biomarker-confirmed mild-to-moderate AD. It informs our future work in an upcoming efficacy trial in an AD population.
Abstract via europepmc.
Exposures
Exposure 1: SUS to bilateral precuneus/posterior cingulate
Target: precuneus, posterior cingulate cortex — “bilateral precuneus/posterior cingulate region”
Device: Sonic Concepts · Sonic Concept Inc., USA · H117 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 286 | ✓✓✓ |
| Pulse duration (ms) | 10 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 10% | ⚑ |
| Sonication duration (s) | 6 | ✓✓✓ |
| Free-field pressure (kPa) | 1,950, 2,600swept | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 780, 1,040swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 21.1, 37.5swept | ✓✓✓⚑ |
Scanning mode: 6-s sonications (10 ms pulses, 10 Hz PRF) moved across a 6 x 6 mm target grid, 30 sonications per session in Cohort 1 and 100 in Cohort 2; four sessions fortnightly. Started at 2.6 MPa free-field PNP, titrated to 1.95 MPa (all of Cohort 2 at 1.95 MPa).
Exposure 2: SUS to bilateral lateral temporo-parietal association cortex (Cohort 2 only)
Target: temporoparietal junction — “bilateral temporo-parietal association cortex”
Device: Sonic Concepts · Sonic Concept Inc., USA · H117 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 286 | ✓✓✓ |
| Pulse duration (ms) | 10 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 10% | |
| Sonication duration (s) | 6 | ✓✓✓ |
| Free-field pressure (kPa) | 1,950 | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 780 | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 21.1 | ✓✓✓ |
Scanning mode: 6-s sonications (10 ms pulses, 10 Hz PRF) moved across a 6 x 6 mm target grid, 30 sonications per session in Cohort 1 and 100 in Cohort 2; four sessions fortnightly. Started at 2.6 MPa free-field PNP, titrated to 1.95 MPa (all of Cohort 2 at 1.95 MPa).
Flags from extraction
exposures[0].free_field.pressure_kpa— Peak negative pressure in free field for three dose levels (100%, 75%, 50%); 1.95 MPa was the dose delivered for nearly all sonications; 2.6 MPa not tolerated.exposures[0].in_situ.pressure_kpa— Derated PNP values are upper bounds ('<=') based on an assumed 64% average skull attenuation measured in sheep skulls, not subject-specific.exposures[0].unspecified_domain.isppa_w_cm2— Table 2 Isppa values (<=37.5, <=21.1, <=9.4 W/cm2) are not explicitly assigned to free field or derated conditions; discussion pairs 21.1 W/cm2 with 'external PNP of 1.95 MPa'.exposures[0].timing.duty_cycle_pct— Duty cycle not stated; not computed.exposures[1].target.terms— Mapped 'temporo-parietal association cortex' to temporoparietal_junction as nearest vocabulary term.auditory_control— Paper reports participants sometimes heard sound; no auditory control was used or described.