Transcranial pulse stimulation modulates spectral signatures of Alzheimer’s disease in the 3×Tg-AD mouse model

BACKGROUND: Large-scale brain network dysfunction is increasingly recognized as an important feature of Alzheimer's disease (AD), offering insight into disease mechanisms and opportunities for targeted therapeutic intervention. The spectral features of this dysfunction remain poorly understood, and how neuromodulatory interventions interact with and reshape these frequency-resolved network signatures has yet to be explored. METHODS: Triple-transgenic (3×Tg-AD) mice underwent resting-state functional MRI to assess functional connectivity, signal power, and variance across frequency bands after acute and longitudinal transcranial pulse stimulation (TPS), a low-intensity single-pulse neuromodulatory intervention. Novel object recognition testing was used to evaluate exploratory drive and short-term recognition memory following repeated TPS or sham treatment. RESULTS: AD mice exhibited widespread functional connectivity loss accompanied by reduced low-frequency resting-state power and variance, together with a redistribution of spectral energy from slow-5 (0.01-0.027 Hz) to slow-4 (0.027-0.073 Hz) activity. TPS modulated these abnormalities by increasing low-frequency power, rebalancing slow-5/slow-4 fractional power, and strengthening network coherence, with the most prominent effects in cingulate, insular, piriform, and striatal regions. TPS effects showed a non-linear, region-dependent emergence across stimulation trains, with the strongest and most consistent modulation appearing after repeated stimulation. Similar spectral rebalancing was observed both after acute and longitudinal stimulation, persisting for up to 5 days. In addition, hippocampal regions that showed minimal acute responses exhibited delayed spectral changes at 24 h, with further modulation at 120 h. TPS-treated 3×Tg-AD mice did not show the decline in object exploration observed in sham-treated animals and showed an exploration-adjusted increase in novel object preference. CONCLUSIONS: Frequency-specific neural dynamics are sensitive markers of AD-related dysfunction and may provide a useful framework for tracking disease-related network abnormalities. TPS selectively modulates low-frequency oscillatory activity and network coherence and is accompanied by preliminary behavioral changes, including preserved exploratory engagement and an exploration-adjusted increase in novel object preference in a separate behavioral cohort. This highlights the potential of combining neuromodulation with spectral network analysis to monitor disease-related network dysfunction and treatment-associated responses.