Noninvasive ultrashort wave neuromodulation enhances glymphatic clearance to alleviate traumatic brain edema and Alzheimer’s pathology

Abstract

The glymphatic system clears cerebral waste, yet strategies to enhance its function remain elusive. Here, we show that 40.68 MHz ultrashort wave (USW) rapidly enhances glymphatic bulk flow in healthy mice within 10 minutes. USW potentiates both glymphatic influx and efflux, concomitant with increased Delta wave neuronal synchronization, as confirmed by local field potentials and electroencephalograms. Chemogenetic silencing confirms that USW-driven glymphatic enhancement depends on neuronal activity, while pharmacological blockade of aquaporin-4 (AQP4) abolishes the effects, revealing dual reliance on neural dynamics and astrocytic water channels. Mechanistically, USW-induced Delta oscillations promote AQP4 polarization, coupling synchronized firing to perivascular AQP4 redistribution. Moreover, USW ameliorates traumatic brain injury–induced cerebral edema and improves cognitive deficits in Alzheimer’s mice by restoring glymphatic function. Our findings establish USW as a non-invasive neuromodulatory strategy for enhancing glymphatic clearance, offering therapeutic potential for neurological disorders characterized by glymphatic dysfunction.