Transcranial focused ultrasound, pulsed at 40 Hz, activates microglia acutely and reduces Aβ load chronically, as demonstrated in vivo

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 similar to 54% of microglia to colocalize with A beta plaque, acutely, and clearing similar to 50% of A beta 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 ms-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 Ab plaque relative to sham ultrasound (36.0 +/- 4.6% versus 14.2 +/- 2.6% [mean +/- standard error], z = 2.45, p < 0.014) and relative to the contralateral hemisphere of treated brain (36.0 +/- 4.6% versus 14.3 +/- 4.0%, z = 2.61, p < 0.009). Chronic application over five days reduced their Ab plaque burden by nearly half relative to paired sham animals (47.4 +/- 5.8%, z = -2.79, p < 0.005). 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 Ab, 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. (C) 2020 The Author(s). Published by Elsevier Inc.