Non-invasive nanosecond transcranial pulsed electric fields: a deep-penetrating, high-field stimulation that suppresses hippocampalβ-amyloid and improves cognitive deficits in Alzheimer's disease model.

Objective.Hippocampalβ-amyloid (Aβ) pathology may induce early circuit dysfunction and memory impairment in Alzheimer's disease (AD), making it a key target for slowing disease progression. However, existing transcranial electrical stimulation approaches, while remaining within safety limits, are insufficient to non-invasively generate sufficiently strong electric fields in deep brain regions. Here, we investigated whether nanosecond transcranial pulsed electric field stimulation (ns-tPFS) could provide a non-invasive deep-target strategy for modulating hippocampal Aβpathology in an AD model.Approach.The ten-month-old 5xFAD mice were selected for delivering repeated ns-tPFS (500 ns, 500 V, 1 Hz). The intracranial electric field exposure was estimated using finite-element modeling (FEM). Treatment effects were evaluated using the Morris water maze,Y-maze, immunofluorescence of Aβdeposition in the hippocampus and cortex, and western blotting of Aβ-related proteins. In addition, the structural responses of Aβoligomers to pulsed electric fields were examined by employing molecular dynamics (MD) simulations, and structural brain safety was assessed by 9.4 T small-animal magnetic resonance imaging (MRI).Main results.ns-tPFS generated transient hippocampal electric fields on the order of 104V m-1. It reduced the hippocampal Aβburden and was associated with coordinated changes in Aβ-related pathways, including decreased amyloidogenic processing and modulated Aβtransport-related receptors. MD simulations further suggested that Aβoligomers are structurally sensitive to nanosecond-scale electric field transients within the hippocampal field range estimated by FEM. These changes were accompanied by improved spatial and working memory in 5xFAD mice. In contrast, under the present stimulation regimen, healthy mice were observed with no detectable cognitive impairment, or macroscopic MRI abnormalities.Significance.ns-tPFS may be a promising non-invasive deep-target electric-field strategy for mitigating hippocampal Aβpathology and improving cognitive performance in an AD mouse model.