Effects of Transcranial Ultrasound Stimulation Pulsed at 40 Hz on Aβ Plaques and Brain Rhythms in 5XFAD Mice

Abstract BackgroundAlzheimer’s disease (AD) is the most common cause of dementia characterized by amyloid-β (Aβ) plaques and tauopathy. Reducing Aβ has been considered a major AD treatment strategy in pharmacological and non-pharmacological treatments. The impairment in the gamma oscillations, which play an important role in perception and cognitive function, has been shown in mouse AD models and human patients. Recently the therapeutic effect of gamma entrainment treatment on the AD mouse model was reported. Given that ultrasound is an emerging modality of neuromodulation, we investigated the effect of ultrasound stimulation pulsed at gamma frequency (40Hz) on an AD mouse model. MethodsWe implanted electroencephalogram (EEG) electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-months-old 5XFAD and wild-type control mice (n=12 and 6, respectively). Six 5XFAD mice were treated with daily two-hour ultrasound stimulation at 40Hz for two weeks, and the other six mice received sham treatment. Soluble and insoluble Aβ levels in the brain were measured by enzyme-linked immunosorbent assay. Spontaneous EEG gamma power was computed by wavelet analysis, and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling. ResultsWe found that total Aβ 42 and 40 levels, especially insoluble, in the treatment group decreased compared to that of the sham treatment group. The reduction in the number of Aβ plaques in PIL also has been shown. In addition, spontaneous gamma power was increased, and brain connectivity was improved. ConclusionsThese results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβ load and improving brain connectivity