Transcranial focused ultrasound, pulsed at 40 Hz, activates microglia acutely and reduces Aβ load chronically, as demonstrated in vivo
M.S. Bobola, L. Chen, C.K. Ezeokeke, T.A. Olmstead, C. Nguyen, A. Sahota, R.G. Williams, P.D. Mourad
Brain Stimulation 2020, 13, 1014-1023 · 10.1016/j.brs.2020.03.016
Abstract
Objective Iaccarino et al. (2016) [1] exposed 1 h of light flickering at 40 Hz to awake 5XFAD Alzheimer's Disease (AD) mouse models, generating action potentials at 40 Hz, activating ∼54% of microglia to colocalize with Aβ plaque, acutely, and clearing ∼ 50% of Aβ plaque after seven days, but only in the visual cortex. Hypothesis Transcranially delivered, focused ultrasound (tFUS) can replicate the results of Iaccarino et al. (2016) [1] but throughout its area of application. Methods We exposed sedated 5XFAD mice to tFUS (2.0 MHz carrier frequency, 40 Hz pulse repetition frequency, 400 μs-long pulses, spatial peak pulse average value of 190 W/cm 2 ). Acute studies targeted tFUS into one hemisphere of brain centered on its hippocampus for 1 h. Chronic studies targeted comparable brain in each hemisphere for 1 h/day for five days. Results Acute application of tFUS activated more microglia that colocalized with Aβ plaque relative to sham ultrasound (36.0 ± 4.6% versus 14.2 ± 2.6% [mean ± standard error], z = 2.45, p Conclusion Our results compare to those of Iaccarino et al. (2016) [1] but throughout the area of ultrasound-exposed brain. Our results also compare to those achieved by medications that target Aβ, but over a substantially shorter period of time. The proximity of our ultrasound protocol to those shown safe for non-human primates and humans may motivate its rapid translation to human studies.
Abstract via europepmc.
Exposures
Exposure 1: tFUS to hippocampus (acute and chronic, 40 Hz pulsed)
Target: hippocampus — “hippocampus”
Device: Sonic Concepts · Sonic Concepts · H148 array (two-annular, 2 MHz) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 2,000 | ✓✓✓ |
| Pulse duration (ms) | 0.4 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 40 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 1.6% | |
| Sonication duration (s) | 5 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 190 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 3 | ✓✓✓ |
| 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 |
Ultrasound delivered for 5 s followed by 5 s of no ultrasound, repeated for 1 h total per session. Acute study: a single 1 h session to one hippocampus (5 tFUS mice, 4 sham). Chronic study: 1 h/day to each hippocampus (both hemispheres) for 5 consecutive days (5 tFUS mice, 5 sham).
Flags from extraction
exposures[0].timing.pulse_duration_ms— The abstract states '400 ms-long pulses' while the Methods states 'pulse lengths of 400 μs'; 400 ms is physically impossible at a 40 Hz PRF (25 ms period), so the Methods value (0.4 ms) was used and the abstract text is likely a unit typo/OCR error.n_sessions_per_subject— Acute study used a single 1 h session while the chronic study used 5 daily 1 h sessions; no single per-subject session count applies across the whole paper.sham_type— Sham ultrasound procedure mechanism (e.g., transducer powered off vs. blocked) is not described.