Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

Abstract

Background Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by amyloid-β (Aβ) plaques and tauopathy. Reducing Aβ has been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches. Impairment of 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 in AD mouse models has been reported. Given that ultrasound is an emerging neuromodulation modality, we investigated the effect of ultrasound stimulation pulsed at gamma frequency (40 Hz) in an AD mouse model. Methods We implanted electroencephalogram (EEG) electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice (n = 12 and 6, respectively). Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily 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. Results We found that the total Aβ42 levels, especially insoluble Aβ42, in the treatment group decreased in pre- and infra-limbic cortex (PIL) compared to that of the sham treatment group. A reduction in the number of Aβ plaques was also observed in the hippocampus. There was no increase in microbleeding in the transcranial ultrasound stimulation (tUS) group. In addition, the length and number of microglial processes decreased in PIL and hippocampus. Encelphalographic spontaneous gamma power was increased, and cross-frequency coupling was normalized, implying functional improvement after tUS stimulation. Conclusion These 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.

Long-term gamma transcranial alternating current stimulation improves the memory function of mice with Alzheimer’s disease

“…Recently, studies have shown that gamma entrainment by optogenetics or visual stimulation influences the phagocytic activity of microglia ( Iaccarino et al, 2016 ). Microglia can be pathogenic or therapeutic ( Erkhratsky and Nedergaard, 2018 ; Park et al, 2021 ), but unfortunately, our histological marker, Iba1, cannot differentiate between subtypes of microglia. We speculate that the activated microglia in the experiments imply a shift in the microglial phenotype from a proinflammatory M1 subtype to an anti-inflammatory M2 subtype.…”

“… Khatoun et al (2017) noted that the results of long-term stimulation and short-term stimulation are different. Mincheol indicated that for 40 Hz band ultrasound stimulation, the 14-day stimulation effect was much better than the 7-day stimulation effect ( Park et al, 2021 ). We found that short-term (7 days) gamma-tACS could not reduce the influence of microglia by Aβ and could not interfere with gamma connections in the brain.…”

Neurotechnological Approaches to the Diagnosis and Treatment of Alzheimer’s Disease

“…As a result of the mechanical mismatch between stiff commercial implanted probes/fibers (1-100 GPa) and the soft brain tissue (∼kPa), tissue damage may occur in addition to foreign-body response and eventually glial scarring and interface encapsulation and isolation from the neural cells (Jorfi et al, 2014a;Shoffstall and Capadona, 2018;Frank et al, 2019). Moreover, new innovations in materials development and fibers/probes fabrication will open the door to better understanding of neural processes without compromising the high fidelity of intracortical interfaces in chronic studies (Jorfi et al, 2014b;Park et al, 2019;Guo et al, 2020). More recently, photoresponsive anti-Aβ agents such as ruthenium (II) complex have shown efficacy to inhibit self-assembly of Aβ monomers to reduce cytotoxicity of Aβ aggregates (Son et al, 2018).…”

“…Jeong et al (2021) also piloted a clinical study of low-intensity transcranial focused ultrasound that Patients demonstrated mild improvement in measures of memory, executive, and global cognitive functions with no reported side effects. Emulating gamma entrainment, Park et al (2021) utilized 40 Hz ultrasound to reduce Aβ 42 in the hippocampus and cortex in 5XFAD mice. Given this result, it appears that gamma entrainment can be achieved via different neurostimulation modalities.…”

Can gamma entrainment of the brain rhythms prevent or alleviate Alzheimer’s disease?

“…[ 12 ] Ultrasound pulsed at gamma frequency can also entrain the brain rhythms noninvasively in AD. [ 13 ] . A clinical trial was performed with fast gamma magnetic stimulation, although no statistically significant improvement in cognition, functionality, and depression was found.…”