ULTRASOUND NEUROMODULATION IN SINGLE CELLS: A MULTISCALE MECHANOTRANSDUCTION MODEL

Low-frequency focused ultrasound is an emerging non-invasive neuromodulation modality for disorders such as epilepsy, Parkinson's, and Alzheimer's disease. Despite growing experimental evidence of efficacy, its underlying biophysical mechanisms remain a major unresolved challenge, largely due to absence of a foundational physical model linking acoustic stimulation to neuronal excitability. To bridge this gap, we developed a computational single excitatory cell model of ultrasound mechanotransduction by coupling membrane-scale mechanics to biophysically realistic ion-channel dynamics. Four key components were considered: (1) modelling ultrasound-induced acoustic radiation force on the neuronal membrane, (2) capturing the membrane’s viscoelastic behaviour, (3) coupling mechanical effects to ion-channel dynamics to predict excitability changes, and (4) validation against prior experimental data for physiological relevance. Our simulations show that local membrane deformations, due to DC acoustic radiation force, generate a time-varying capacitive current insufficient alone to trigger action potentials. Critically, membrane deformation also activates mechanosensitive channels (Yoo et al., Nat. Commun. 2022), including inhibitory K2P and excitatory Piezo, initiating a multistage nonlinear cascade that drives secondary activation of TRPC1 and TRPP1/2 channels. This produces sustained depolarization and enhanced calcium influx, which subsequently recruits TRPM4 and low-voltage-activated T-type Ca²⁺ channels, enabling threshold crossing and engagement of voltage-gated L-type Ca²⁺ and Na⁺ channels. Channel kinetics and conductances were derived from published experimental studies, while intracellular calcium dynamics and neuron firing behaviour were calibrated for consistency with reported electrophysiological and imaging data. Together, these results highlight a channel-specific pathway linking ultrasound-induced membrane deformation to neurostimulation, and lay the groundwork for further network-level investigations.