Modulatory Effect of Low-Intensity Transcranial Ultrasound Stimulation on Behaviour and Neural Oscillation in Mouse Models of Alzheimer’s Disease

Huifang Yang, Jiaqing Yan, Hui Ji, Mengran Wang, Teng Wang, Huiling Yi, Lanxiang Liu, Xin Li, Yi Yuan

IEEE Transactions on Neural Systems and Rehabilitation Engineering 2024, 32, 770-780 · 10.1109/tnsre.2024.3363912

rodentalzheimers diseasebehaviourinvasive electrophysiologyhistology molecular

Abstract

Transcranial ultrasound stimulation (TUS) is a noninvasive brain neuromodulation technique. The application of TUS for Alzheimer's disease (AD) therapy has not been widely studied. In this study, a long-term course (28 days) of TUS was used to stimulate the hippocampus of APP/PS1 mice. We examined the modulatory effect of TUS on behavior and neural oscillation in AD mice. We found that TUS can 1) improve the learning and memory abilities of AD mice; 2) reduce the phase-amplitude coupling of delta-epsilon, delta-gamma and theta-gamma frequency bands of local field potential, and increase the relative power of epsilon frequency bands in AD mice; 3) reduce the spike firing rate of interneurons and inhibit the phase-locked angle deflection between the theta frequency bands and the spikes of the two types of neurons that develops with the progression of the disease in AD mice. In summary, we demonstrate that TUS could effectively improve cognitive behavior and modulate neural oscillation with AD.

Abstract via europepmc.

SpeciesAPP/PS1 transgenic mouse (C57BL/6 background)

Subjects12 animals

Sessions per subject28

Randomisedyes

Blindingnot reported

Sham / controlnone

Auditory controlramped pulses

Readout timingoffline

Anaesthesiaboth

Readoutsbehaviour, invasive electrophysiology, histology molecular — Open field test; Morris water maze; fear conditioning test; local field potential (LFP) relative power and cross-frequency phase-amplitude coupling; single-unit spike firing rate and theta phase-locking; ELISA for amyloid-beta and Tau

Direction of effectinhibitoryTUS reduced the elevated interneuron firing rate seen in AD mice, ameliorated abnormal theta phase-locking of interneuron and pyramidal neuron spikes, improved phase-amplitude coupling of delta-epsilon/delta-gamma/theta-gamma bands, and improved spatial learning/memory and anxiety-related behaviour in AD mice.

Adverse eventsnot reported

Exposures

Exposure 1: TUS to hippocampus (ADsti group)

Target: hippocampus — “hippocampus”
Device: Olympus / Panametrics · Olympus · V301-SU ✓

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	500	✓✓✓
Pulse duration (ms)	50	✓✓✓
Pulse repetition frequency (Hz)	1	✓✓✓
Duty cycle (%)	5pulse duration × PRF gives 5%	✓✓✓
Sonication duration (s)	900	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	not reported
Free-field Isppa (W/cm²)	not reported
Free-field Ispta (W/cm²)	not reported
In-situ estimate	measurementsingle value
In-situ pressure (kPa)	300	✓✓✓
In-situ Isppa (W/cm²)	6	✓✓✓
In-situ Ispta (W/cm²)	not reported

Protocol, in the paper’s words

Ultrasound treatment was performed with a 0.5-MHz unfocused piezoelectric transducer with a 50-msec burst at a 5% duty cycle and a repetition frequency of 1 Hz. Low-intensity TUS was applied to the hippocampus of the ADsti group for a sonication time of 15 min at an ultrasound intensity of 0.3 MPa daily for a period of 28 days (D0-D27).

Flags from extraction

n_subjects — An additional 6 APP/PS1 mice received a different ultrasound waveform (trapezoidal pulses) solely to test for auditory confounds; these are not counted in n_subjects for the main hippocampal TUS exposure
readout_timing — TUS was performed after the fear conditioning test and EEG acquisition on each collection day, so behavioural/EEG readouts were largely offline relative to sonication, though this alternation happened within the same day across the 28-day course