Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice
Mincheol Park, Gia Minh Hoang, Thien Nguyen, Eunkyung Lee, Hyun Jin Jung, Youngshik Choe, Moon Hwan Lee, Jae Youn Hwang, Jae Gwan Kim, Tae Kim
Translational Neurodegeneration 2021, 10 · 10.1186/s40035-021-00274-x
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.
Abstract via europepmc.
Exposures
Exposure 1: unfocused transcranial ultrasound to whole brain, 40 Hz gamma entrainment, 5xFAD mice
Target: whole brain or unfocused — “entire brain (unfocused, skull-mounted transducer)”
Device: other named manufacturer · Steiner & Martins Inc. · SMD07T03R411 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 300 | ✓✓✓ |
| Pulse duration (ms) | 3 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 40 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 12% | ⚑ |
| Sonication duration (s) | 0.2 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| 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 | |
| Isppa, domain unspecified (W/cm²) | 1.2 | ✓✓✓ |
| Ispta, domain unspecified (W/cm²) | 0.0144 | ✓✓✓ |
A piezo-ceramic disc transducer implanted on the skull delivered 300-kHz ultrasound pulsed at 40 Hz with a 3-ms pulse width. These pulses were organized into 200-ms-ON/800-ms-OFF sub-cycles, which were themselves repeated in 10-s-ON/30-s-OFF stimulation blocks (180 repeats), giving a 2-h daily session repeated for 14 days. A computational simulation estimated that >60% of ultrasound pressure was transmitted through the mouse skull, affecting 9% (-6 dB) or 45% (-12 dB) of brain volume.
Flags from extraction
exposures[0].timing.sonication_duration_s— the protocol has multiple nested timing levels (3-ms pulses at 40 Hz forming a 200-ms-ON/800-ms-OFF sub-cycle, itself forming 10-s-ON/30-s-OFF blocks repeated over a 2-h daily session); this does not map onto a single 'uninterrupted train' duration, so left not_reported and described fully in protocol_description.exposures[0].timing.waveform— classified as pulsed based on the stated 40-Hz pulse repetition frequency and 3-ms pulse width; the nested 200/800 ms and 10/30 s block structure could also be described as other_patterned.exposures[0].timing.duty_cycle_pct— not explicitly stated as a percentage by the paper; not computed from pulse width and PRF.exposures[0].in_situ— a computational simulation reported that >60% of ultrasound pressure was transmitted through the mouse skull and that 9% or 45% of brain volume was affected depending on threshold, but no absolute in-brain pressure or intensity value (kPa or W/cm2) was given, so in_situ numeric fields are not_reported.sham_type— the paper states only that six mice 'received sham treatment' without describing the sham mechanism (e.g. inactive transducer vs. other).